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The role of the tumor microenvironment in the metastasis of pancreatic cancer and immunotherapy
CHAPTER 5
The role of the tumor microenvironment in the metastasis of pancreatic cancer and immunotherapy Sermin Tetik1, Nilgun Tekkesin2, 3 1
Department of Biochemistry, Faculty of Pharmacy, Marmara University, Istanbul, Turkey; 2Department of Biochemistry, Memorial Hospital, Istanbul, Turkey; 3School of Medicine, Nisantasi University, Istanbul, Turkey
Abstract Pancreatic cancer is the most aggressive type of cancer, with egregious survival rates, and is notoriously difficult to treat. Patients with pancreatic cancer are generally diagnosed at an advanced stage. Unfortunately, only a small portion of them can be treated with surgical resection. Current therapeutic approaches in pancreatic cancer involve the biochemical mechanism of the tumor microenvironment, therapeutic agents, and immunotherapy. The immunosuppressive microenvironment of pancreatic cancer is composed of T-regulatory cells, chemokines, neoplastic epithelial cells, fibroblasts, platelets, tumor-associated macrophages, pericytes, natural killer cells, and other immune cells. Pancreatic cancer is resistant to single-checkpoint immunotherapies and other therapeutic approaches such as vaccination. In this chapter, we discuss the tumor microenvironment/immunity and the immune escape mechanism of pancreatic cancer that limits the effectiveness of immunotherapeutic methods.
Keywords: Immune suppressors; Immune surveillance; Immunotherapy; Pancreatic cancer; Tumor microenvironment.
List of abbreviations BCL-2 B-cell lymphoma CAFs Cancer-associated fibroblasts CCL-2 Chemokine chemokine (CeC motif) ligand-2 CTLA4 Cytotoxic T lymphocyte antigen 4 DCs Dendritic cells FDA Food and Drug Administration IDO Indoleamine-2,3 dioxygenase IFN-gamma Interferon-gamma IL Interleukin G.P. Nagaraju, S. Ahmad (eds.) Theranostic Approach for Pancreatic Cancer ISBN 978-0-12-819457-7 https://doi.org/10.1016/B978-0-12-819457-7.00005-0
Copyright © 2019 Elsevier Inc. All rights reserved.
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LMPs Latent membrane proteins MDSCs Myeloid-derived suppressor cells MHC-1 Major histocompatibility complex-1 NSCLC Nonesmall cell lung cancer PD-1 Programmed cell death protein-1 PDA Pancreatic ductal adenocarcinoma PD-L1 Programmed cell death protein-ligand STAT3 Signal transducer and activator of transcription TAMs Tumor-associated macrophages Tregs T-regulatory cells
Introduction Cancer cells are resistant to cell death owing to enhanced inflammation in series mutations in proto-oncogenes and oncogenes. Several tumor types also have hallmark cascades, which include the sustainment of proliferative signals, evasion of growth suppressors, avoidance of immune destruction, enabling of replicative immortality, tumor-promoting inflammation, activation of invasion and metastasis, induction of angiogenesis, genome instability and mutations, deregulation of cellular energetics, and resistance to cell death [1,2]. Cancer research has focused on the tumor microenvironment and the complex interaction between it and the tumor. The tumor microenvironment consists of multiple cell types such as vascular endothelium, inflammatory cells, and mesenchymal cells (fibroblasts of various types). In addition to these cells, resident fibroblasts, pericytes, leukocytes, and extracellular matrix components contribute to the development of cancer progression through the tumor microenvironment [3,4]. Ongoing research aims to shed light on the relation between the pancreatic tumor microenvironment and cancer metastasis that pancreatic ductal adenocarcinoma (PDA) develops, depending on the tumor microenvironment [5]. The tumor microenvironment contributes aggressively to the development of tumor progression and metastasis rather than acting as a nonparticipant. Therefore, therapeutic approaches targeting the tumor microenvironment as well as metastasis have great potential. We need to know how the tumor microenvironment works, operates, and functions, with all of its complex interactions (signals, stromal cells, metabolites, etc.) and consequently, how we can make our therapies more effective. To this end, we will discuss the role of the tumor microenvironment in managing tumor development and it relation to cancer immunotherapy.
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Future studies elucidating the mechanisms of the metastasis of pancreatic cancer will provide new therapeutic approaches.
What is the role of the tumor microenvironment in regulating cancer cell metabolism? Neoplastic and stromal cells combine to form a tumor structure. Stromal cells are related to immune system cells, because these cells contain cancer associated with mesenchymal cells, especially fibroblasts, myofibroblasts, endothelial cells, pericytes, and inflammatory cells that influence disease intensity. Cancer or tumor cells and all derived components from normal cells must recruit to a primary tumor site to form the tumor microenvironment [6]. After that recruit, these cells can efficiently secrete stimulatory growth factors, cytokines, and chemokines. On the other hand, activated fibroblasts can be modulated by tumor cells and transformed into microenvironment cancer-associated fibroblasts (CAFs) [7]. Hypoxic conditions trigger the secretion of interleukin-6 (IL-6) and induce much more CAF formation. When CAFs are stimulated, they begin modifying angiogenesis via cell recruits (Table 5.1.) [8]. Another important factor for regulating the recruitment of endothelial cells and metastasis is microRNA synthesis in the tumor microenvironment. Publications imply that the tumor microenvironment supports tumor growth and immunity depression [9]. In tumor progression, chemokines and cytokines, which are activated inflammatory cells (such as macrophages, tumor-associated macrophages [TAMs], and vascular endothelial growth factor), also contribute to tumor mass and flow into the tumor site to promote the type of tumor microenvironment conditions described earlier. Pericytes such as endothelial cells have a role in the tumor microenvironment and induce cancer metastasis. Platelets can release several factors such as chemokines and several growth factors which, when activated, contribute to metastasis. Fig. 5.1 shows that the tumor microenvironment regulates cancer metastasis [10,11].
Tumor immunology for metastatic pancreatic cancer Pancreatic cancer is predicted to be the third leading cancer type after breast cancer in the near future in the United States [12].
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Table 5.1 Microenvironment components in pancreatic cancer. Ingredients Examples
Immune cells
Vasculature Mesenchymal cells Extracellular matrix proteins
Chemokine-interleukin
Natural killer cell Myeloid-derived suppressor cells Neutrophils Tumor-associated macrophages Mast cells T Lymphocytes (primarily regulator) Stromal cell-derived factor-1 Major histocompatibility complex 1 Endothelial cells Pericytes Cancer associated fibroblasts Pancreatic stellate cells (PSCs) Collagens I, III, IV Fibroblast-associated protein Fibronectin Growth factors (hepatocyte growth factor) Hyaluronic acid Laminin MMP-2, MMP-9, MMP-13 Secreted protein acidic and rich in cysteine eosteonectin Trombospondin-1/2 Platelets Transforming growth factor-b Chemokine chemokine motif 2 Macrophage colony-stimulating factor Monocyte chemotactic protein 1 IL-6 IL-10
IL, interleukin; MMP, matrix metalloproteinase.
Conventional treatment of pancreatic cancer is limited to stopping the invasion of tumor cells in the body. Evidence in the field of tumor immunology research has improved our knowledge of how tumor cells circumvent immune surveillance and how tumors directly repress immune progression [13,14]. Because of immune system mechanisms, immunotherapy strategies have been developed to suppress antitumor immunity of the tumor microenvironment and control tumor evasion in the body [15e17].
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Figure 5.1 The tumor microenvironment supports progressive pancreatic cancer metastasis. Emts, epithelial to mesenchymal transitions.
The mechanism of cancer cells has the property of uncontrolled expression. Cancer cells are simply mutated, modified, misfolding proteins. Immune surveillance is the first step to filtrate malignant cells, but tumor cells have developed strategies to escape from the immune elimination system and continue cancer progression [18] (Fig. 5.2). In some patients with cancer, the presence of tumor-associated antigens (TAAs) can be considered evidence of an immune response in many types of pancreatic cancer [19]. Tumor cells express major histocompatibility complex (MHC), which binds peptide from outside and interacts at the cell surface with T cells of the immune system via T-cell antigen receptors. T-cell activation is necessary for this interaction, but not sufficient. However, the signal that effects T-cell activation is dispatched by dendritic cells (DCs), which are the key constituents of the immune response of a cell [20]. Tumor cells can also escape from immune recognition by downregulating antigens such as MHC I pathway proteins or latent membrane
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Figure 5.2 Immunotherapy strategies to overcome tumor cell invasion. Lenf, lymphatic.
proteins (LMP2 and LMP7) [21]. T-cell effectors recognize these tumor antigens (CD8þ or CD4þ T cells) [22]. If these antigens are lacking or genetic stability is lost, cell division is disrupted. After this, tumor cells exhibit unlimited division. There is increasing evidence that the tumor microenvironment of pancreatic cancer is much more suited to immune escape [23].
Immunoediting Studies have shown that patients with pancreatic cancer have an abundance of tumor-reactive T lymphocytes in bone marrow, leukocyte infiltrate, regulatory T cells (Tregs), TAMs, and myeloid-derived suppressor cells (MDSCs) [24e26]. MDSC levels are elevated in both the blood and the tumor microenvironment of patients with pancreatic cancer, which inhibits T-cell activation. Treg cell numbers grow significantly to suppress host immune activity [27,28]. Changes in the immunogenicity of cancer cells that provoke immune resistance are collectively known as tumor immunoediting. In this phase, called the elimination phase, proteins are mutated or modified owing to several attacks on the tumor cell. However, immune surveillance copes with tumor cells via native immune forces [29].
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Immune surveillance of this system forms innate immune cells such as NK, NKT, gd-T, and DCs [30,31]. Native immune cells recognize tumor cells and the battle is partially started by native immune cells. The battle includes several warriors such as tumor antigen-specific T cells CD4þ and CD8þ, which are recruited to the tumorigenesis site to eliminate tumor cells [22,32]. The second phase, equilibrium, is started while elimination of tumor cells continues by immune surveillance. During this period, some tumor cells have increased resistance to the elimination process owing to the mutated tumor cell [33]. These tumor cell variants are associated with a nonimmunogenic phenotype. Therefore, tumor antigens are incapable of downregulating the tumor cell number and epigenetic alterations, accompanied by increased tumorigenesis. This step is the longest process in cancer immunoediting; it will stop when the final phase called escape, begins [34,35]. In this phase, cancer cells are transformed genetically as well as epigenetically, and are inclined to escape from immune surveillance. T-cell antigen expression drops even further, and tumorigenesis may develop more freely owing to extrinsic factors compared with the elimination phase [36]. Tumor cells from the tumor microenvironment stimulate immune system molecules to release immunosuppressive cytokines such as IL-1, IL-6, and IL-10 or induce immune checkpoint molecules such as the B7 family [37,38]. Manipulated tumor cells have increased resistance to apoptosis by overexpression of signal transducer and activator of transcription 3 or B-cell lymphoma 2. The immune escape phase is expanded (Table 5.2) [39].
Development of strategies that target immune checkpoints The immune system is regulated by stimulatory and inhibitory signals. Foreign antigens stimulate immune system cells, especially DCs that manage T-cell induction, to respond to and clear unwanted tumor cells. On the other hand, coinhibitory signals of antitumor response are regulated by the numbers of inhibitory molecules. B7-1 and B7-2 are bound to their receptor (CD28) on T cells to form a costimulatory message. However, they can generate coinhibitory messages when they bind to cytotoxic T lymphocyte antigen-4 (CTLA4) on T cells. The T-cell activation rate and programmed cell death protein I (PD-1) expression are reduced upon coinhibitory signals whereas CTLA4 activation is increased and immune activation is interrupted [40,41].
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Table 5.2 Mechanisms of immune tolerance in pancreatic cancer [24,38]. Processes involved in immune tolerance Regulatory ingredients
Change in cytokines and chemokines regulation
Tolerance persuaded with DC differentiation and regulation
Downregulation of costimulatory signals Immune checkpoints at molecular level
Cellular checkpoints of immune activity
Change metabolism in immune cells
Upregulation of transforming growth factor-b signaling and IL-10 Downregulation of IL-12 and IFN-gamma Release of IL-1, IL-6, IL-10 Naive DCs Upregulation of vascular endothelial growth factor, cyclooxygenase-2, IL-6, and macrophage colony-stimulating factor Downregulation of granulocyte macrophage colony-stimulating factor, IL-4, IL-12, and IFN-gamma Downregulation of B7-1 and B7-2 Presence and/or upregulation of cytotoxic T-lymphocyte antigen-4, PD-L1/B7eH1, PD-L2/B7eH3, B7eH4, programmed cell death protein-1 Overexpression of signal transducer and activator of transcription 3 and B-cell lymphoma 2 Downregulation of Tregs Elevated of myeloid-derived suppressor cell levels Tumor-associated macrophage Upregulation of indoleamine-2,3 dioxygenase, arginase, nitric oxide synthase, etc. Downregulation of MHC 1, major histocompatibility complex 1, LMP2 and LMP7
DCs, dendritic cells; IFN-gamma, interferon-gamma; IL, interleukin; PD-L1, programmed cell death protein-ligand 132 LMP, latent membrane protein family; Treg, T-regulatory cell.
Immune mechanisms are based on immune checkpoint strategies for the treatment of tumor cells. CTLA4 is a key coinhibitory molecule that manages immune regulation. Immunological checkpoints have two important basic goals. First, T-cell activation is generated for self-antigens. Second, when normal T-cell response is increased, another response suppresses foreign pathogens. Tumor cells use this opportunity to evade tissues
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during the suppression phase. All balance is disturbed, and arrows are turned in the direction of coinhibitory signals [42]. Improved immune tolerance is critical for overcoming tumor invasion in patients with pancreatic cancer, with egregious survival rates and poor therapy efficiency. The purpose of the treatment strategy’s is to generate downregulated CTLA4 in tumor invasion, which demonstrates the important role of CTLA4 in tumor immune evasion [43,44]. CTLA4 blocking antibodies are used to improve the rejection of tumors, a technique currently under clinical investigation. There are two antibodies: ipilimumab and tremelimumab. However, CTLA4 monotherapy is supported by generations of antitumor immunity in some tumor models whereas monotherapy is ineffective against mammary tumors and melanoma [45]. Bengsch et al. presented results on pancreatic ductal adenocarcinoma (PDA) mouse models, the most frequent type of pancreatic cancer, blocking CTLA4 to induce T-cell tumor infiltration. However, clinical trials with CTLA4 immunotherapy have failed [46]. Another result is given in a genetically engineered PDA murine model, in which the effects of CTLA4 antibodies against tumor growth have also been unsatisfactory [26]. Contrary to several negative results, a different study showed that induced T-cell-response with CD40 monoclonal antibodies plus gemcitabine and NAB-paclitaxel is highly success in overcoming PDA resistance to CTLA4 immunotherapy [47]. As discussed earlier, T-cells regulate antitumor activity through costimulatory signals such as B7-1/B7-2- and CTLA4, which affect each other and tumor cells and other cells within the tumor microenvironment. PD-11 and its ligand, programmed cell death protein-ligand 1 (PD-L1) (B7/H1) are coinhibitory signals that belong to the B7 family. Overexpression of PDL-1 in cancer is formed after activation of T cells, B cells, and macrophages. Results of PD-L1 activation are accompanied by potent immune suppression and tumor immune escape. PD-1 is also expressed by pancreatic tumor cytotoxic infiltrates [48,49]. Pembrolizumab and nivolumab are both humanized monoclonal antibodies with the aim of blocking human PD-1. Pembrolizumab is approved by the Food and Drug Administration (FDA) to treat PD-L1epositive metastatic nonesmall cell lung cancer (NSCLC) as part of the first- and second-line therapies, and advanced melanoma. Nivolumab is also approved
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by the FDA to treat NSCLC as a second-line therapy for recurrent squamous cell carcinoma of the head and neck [50,51]. These antibodies have lower toxicity compared with anti-CTLA4 antibodies. Therefore, research into PD-1 blockage with tumor vaccines has reached a milestone [52,53]. Tregs maintain a high expression of CD4þCD25þFoxP3þ precursors that prevent autoimmune diseases. However, several studies showed that these cells are recruited to the tumor site and alter antitumor immune response [54,55]. Targeted strategies are not able to increase or decrease Tregs specifically to regulate immune checkpoints in human cancer patients. CD25þ antibodies are used to drain Tregs in human vaccine trials, but these human vaccination strategies employing targeted CD25þ antibodies are inefficient for depleting Tregs. This ineffective result was shown in another clinical trial using a protein that binds CD25þ, called ONTAK [56,57]. In yet another targeting strategy, the basic objective is also to inhibit Tregs by a chemotherapeutic agent, cyclophosphamide, to regulate the immune checkpoint response. Unfortunately, it has failed [58]. Indoleamine-2,33 dioxygenase (IDO) activity is another critical regulator of both tumor cell proliferation and immune cell regulation. Overexpression of IDO supports the tumor microenvironment. All approaches point to the fact that the tumor microenvironment is the medium in which immune tolerance is improved [59]. Overexpression of IDO results in reduced tryptophan levels. Owing to tryptophan metabolism, L-arginine metabolism is also impaired, which renders it unable to contribute positively to the tumor microenvironment. L-Arginine metabolism is regulated by two enzymes, arginase and nitric oxide synthase, both of which are overexpressed. Studies demonstrated the critical role that the two enzymes have in regulating the immune response [60]. This is supported further by evidence that when both arginine and nitric oxide synthase are blocked by a combination of nitroaspirin and sildenafil via a tumor vaccine or adaptive T-cell therapy, the survival rate of tumor-bearing mice improves [61].
Conclusion The immune system has an important role in regulating the tumor microenvironment. Pancreatic cancer exhibits high-intensity downregulation of the immune system whose job is to tag and capture malignant cells.
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Therefore, therapeutic approaches have not yet produced the desired clinical benefit, except for some patients. Tumors and the tumor microenvironment cause disruption of antigenicity and immunogenicity through their ability to establish an immunosuppressive microenvironment. The mechanisms of immune system depression by the tumor microenvironment should be elucidated to enable the conception of new therapeutic approaches. It appears that treatments of metastatic pancreatic cancer based on improving immune tolerance will yield better clinical outcomes. New therapeutic strategies may focus on personalized immune profiling of the tumor microenvironment and mapping their antigenicity and immunogenicity, to distinct benefit.
Conflict statement The authors declare that they have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the chapter.
Acknowledgments This work has not been funded by any financial organization. Murat Köksal (M.Sc. Pharm.) participated in drafting the chapter. Ödül Tetik (B.Sc. Math.) edited the manuscript. Both authors gave final approval of the submitted version.
References [1] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646e74. [2] Hanahan D, Weinberg RA. The Hallmark of cancer. Cell 2000;100:57e70. [3] Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012;12:253e68. [4] Yuan Y, Jiang Y, Sun C, Chen Q. Role of the tumor microenvironment in tumor progression and the clinical applications. Oncology Rep 2016;35:2499e515. [5] Ren B, Cui M, Yang G, Wang H, Feng M, You L, Zhao Y. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer 2018;17:108. [6] Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19:1423e37. [7] Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 2006;5:1597e601. [8] Ko AH. Progress in the treatment of metastatic pancreatic cancer and the search for next opportunities. J Clin Oncol 2015;33(16):1779e86. [9] Png KJ, Halberg N, Yoshida M, Tavazoie SF. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature 2011;481:190e4.
108
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[10] Coussen LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 2013:286e91. [11] Jeon S-M. Hay Nç Expanding the concepts of cancer metabolism. Exp Mol Med 2018;32:1e3. [12] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7e30. [13] Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Investig 2007;117:1137e46. [14] Chew V, Toh HC, Abastado JP. Immune microenvironment in tumor progression: characteristics and challenges for therapy. J Oncol 2012;2012:608406. [15] Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2014;21:687e92. [16] Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HMCS, Signori E, Honokik K, Georgakilas AG, Amin A, Helferich WG, Boosani CS, Guha G, Ciriolo MR, Chen S, Mohammed SI, Azmi AS, Keith WN, Bilsland A, Bhaktaq D, Halicka D, Fujii H, Aquilanor K, Ashraf SS, Nowsheen S, Yango X, Choiz BK, Kwonaz BS. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015;35:S185e98. [17] Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015;27:450e61. [18] Lowy AM, Leach SD, Philip PA, Pollock RE, editors. Pancreatic cancer. 1st ed. New York: Springer; 2008. [19] Zhang JY, Tan EM. Autoantibodies to tumor-associated antigens as diagnostic biomarkers in hepatocellular carcinoma and other solid tumors. Expert Rev Mol Diagn 2010;10:321e8. [20] Tai Y, Wang Q, Korner H, Zhang L, Wei W. Molecular mechanisms of T cells activation by dendritic cells in autoimmune diseases. Front Pharmacol 2018;9:642. [21] Ferrington DA, Gregerson DS. Immunoproteasomes: structure, function, and antigen presentation. Prog Mol Biol Transl Sci 2012;109:75e112. [22] Hadrup S, Donia M, Thor Straten P. Effector CD4 and CD8 T cells and their role in the tumor microenvironment. Cancer Microenviron 2012;6(2):123e33. [23] Restifo NP, Esquivel F, Kawakami Y, Yewdell JW, Mulé JJ, Rosenberg SA, Bennink JR. Identification of human cancers deficient in antigen processing. J Exp Med 1993;177:265e72. [24] Neoptolemos JP, Urrutia R, Abbruzzese JL, Büchler MW, editors. Pancreatic cancer. 2nd ed. New york: Springer; 2018. [25] Hall M, Liu H, Malafa M, Centeno B, Hodul PJ, Pimiento J, Plion-Thomas S, Samaik AA. Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors. J Immunother Cancer 2016;4:61. [26] Martinez-Bosch N, Vinaixa J, Navarro P. Immune evasion in pancreatic cancer: from mechanisms to therapy. Cancers (Basel) 2018;10(1):6. [27] Xuhao N, Jinhui T, Joseph B, Qian C, Park BV, Zhiguang L, Nailing Z, Andriana L, Anjali R, Ping W, Ying Z, Xuehong Z, Zingmei W, Paolo V, Cui Ping Y, Huabin L, Drew P, Ling L, Duojia PFP. YAP is essential for Treg-mediated suppression of Antitumor I_mmunity. Cancer Discov 2018;8:1026e43. [28] Feng S, Cheng X, Zhang L, Lu X, Chaudhary S, Teng R, Frederickson C, Champion MM, Zhao R, Cheng L, Gong Y, Deng H, Lu X. Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers. Proc Natl Acad Sci USA 2018;115:10094e9. [29] Becker JC, Andersen MH, Schrama D, Thor Straten P. Straten Immune-suppressive properties of the tumor microenvironment. Cancer Immunol Immunother 2013;62:1137e48.
The role of the tumor microenvironment in the metastasis of pancreatic cancer
109
[30] Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, Deng W, Wang L, Shifrin N, Raulet DH. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol 2014;122:91e128. [31] McEwen-Smith RM, Salio M, Cerundolo V. The regulatory role of invariant NKT cells in tumor immunity. Cancer Immunol Res 2015;3:425e35. [32] Kohlgruber AC, Donado CA, Lamarche NM, Brenner MB, Brennan PJ. Activation strategies for invariant natural killer T cells. Immunogenetics 2016;68:649e63. [33] Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011;331:1565e70. [34] Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science 2013;339(6127):1546e58. [35] Chatterjee A, Rodger EJ, Eccles MR. Epigenetic drivers of tumorigenesis and cancer matastasis. Semin Canc Biol 2018;51:149e59. [36] Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007;121(1):1e14. [37] Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577e81. [38] Bekaii-Saab T, El-Rayes B, editors. Current and emerging therapies in pancreatic cancer. eBook. 1st ed. Springer; 2018. [39] Nurieva R, Wang J, Sahoo A. T-cell tolerance in cancer. Immunotherapy 2013;5(5):513e31. [40] Johnson III BA, Yarchoan M, Lee V, Laheru DA, Jaffee EM. Strategies for increasing pancreatic tumor immunogenicity. Clin Cancer Res 2017;23:1656e69. [41] Lippe MJ, Le DT, editors. Pancreatic cancer: a patient and his doctor balance and truth. 1st ed. Baltimore: The John Hopkins University Press; 2011. [42] Wu Y, Zheng Z, Jiang Y, Chess L, Jiang H. The specificity of T cell regulation that enables self-nonself discrimination in the periphery. Proc Natl Acad Sci USA 2009;106:534e9. [43] Noh KH, Kang TH, Kim JH, Pai SI, Lin KY, Hung CF, Wu TC, Kim TW. Activation of Akt as a mechanism for tumor immune evasion. Mol Ther 2008;17:439e47. [44] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012b;366. 2443e54. [45] Callahan MK, Wolchok JD, Allison JP. Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol 2010;37:473e84. [46] Bengsch F, Knoblock DM, Liu A, McAllister F, Beatty GL. CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. Cancer Immunol Immunother 2017;66:1609e17. [47] Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, Clendenin C, Stanger BZ, Furth EE, Wherry EJ, Vonderheide RH. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol Res 2015;3:399e411. [48] Lu C, Paschall AV, Shi H, Savage N, Waller JL, Sabbatini ME, Oberlies NH, Pearce C, Liu K. The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion. J Natl Cancer Inst 2017;109:djw283.
110
Theranostic Approach for Pancreatic Cancer
[49] Munir S, Andersen GH, Ö M, Donia M, Frøsig TM, Larsen SK, Klausen TW, Svane IM, Andersen MH. HLA-restricted CTL that are specific for the immune checkpoint ligand PD-L1 occur with high frequency in cancer patients. Cancer Res 2013;73:1764e76. 15. [50] Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, Keegan P, Pazdur R. FDA approval summary: nivolumab for the treatment of metastatic nonsmall cell lung cancer with progression on or after platinum-based chemotherapy. Oncol 2016;21:634e42. [51] Fessas P, Lee H, Ikemizu S, Janowitz T. A molecular and preclinical comparison of the PD-1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol 2017;44:136e40. [52] Bowyer S, Prithviraj P, Lorigan P, Larkin J, McArthur G, Atkinson V, Khou M, Diem S, Ramanujam S, Kong B, Liniker E, Guminski A, Parente P, Andrews MC, Parakh S, Cebon J, Long GV, Carlino MS, Klein O. Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. Br J Cancer 2016;114:1084e9. [53] Ye Z, Qian Q, Jin H, Qian Q. Cancer vaccine: learning lessons from immune checkpoint inhibitors. J Cancer 2018;9:263e8. [54] Ziani L, Chouaib S, Thiery J. Alteration of the antitumor immune response by cancerassociated fibroblasts. Front Immunol 2018;9:414. [55] Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011;241:260e8. [56] Lansigan F, Stearns DM, Foss F. Role of denileukin diftitox in the treatment of persistent or recurrent cutaneous T-cell lymphoma. Cancer Manag Res 2010;2:53e9. [57] Lutz MB, Baur AS, Schuler-Thurner B, Schuler G. Immunogenic and tolerogenic effects of the chimeric IL-2-diphtheria toxin cytocidal agent Ontak®on CD25þ cells. OncoImmunology 2014;3:e28223. [58] Pitt JM, Vétizou M, Daille`re R, Roberti MP, Yamazaki T, Routy B, Lepage P, Gomperts Boneca I, Chamaillard M, Kroemer G, Zitvogel L. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity 2016;44:1255e69. [59] Devaud C, John LB, Westwood JA, Darcy PK, Kershaw MH. Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy. OncoImmunology 2013;2:e25961. [60] Kim SH, Roszik J, Grimm EA, Ekmekcioglu S. Impact of l-arginine metabolism on immune response and anticancer immunotherapy. Front Oncol 2018;8:67. [61] Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 2006;27:2691e702.
The role of the tumor microenvironment in the metastasis of pancreatic cancer and immunotherapy Sermin Tetik1, Nilgun Tekkesin2, 3 1
Department of Biochemistry, Faculty of Pharmacy, Marmara University, Istanbul, Turkey; 2Department of Biochemistry, Memorial Hospital, Istanbul, Turkey; 3School of Medicine, Nisantasi University, Istanbul, Turkey
Abstract Pancreatic cancer is the most aggressive type of cancer, with egregious survival rates, and is notoriously difficult to treat. Patients with pancreatic cancer are generally diagnosed at an advanced stage. Unfortunately, only a small portion of them can be treated with surgical resection. Current therapeutic approaches in pancreatic cancer involve the biochemical mechanism of the tumor microenvironment, therapeutic agents, and immunotherapy. The immunosuppressive microenvironment of pancreatic cancer is composed of T-regulatory cells, chemokines, neoplastic epithelial cells, fibroblasts, platelets, tumor-associated macrophages, pericytes, natural killer cells, and other immune cells. Pancreatic cancer is resistant to single-checkpoint immunotherapies and other therapeutic approaches such as vaccination. In this chapter, we discuss the tumor microenvironment/immunity and the immune escape mechanism of pancreatic cancer that limits the effectiveness of immunotherapeutic methods.
Keywords: Immune suppressors; Immune surveillance; Immunotherapy; Pancreatic cancer; Tumor microenvironment.
List of abbreviations BCL-2 B-cell lymphoma CAFs Cancer-associated fibroblasts CCL-2 Chemokine chemokine (CeC motif) ligand-2 CTLA4 Cytotoxic T lymphocyte antigen 4 DCs Dendritic cells FDA Food and Drug Administration IDO Indoleamine-2,3 dioxygenase IFN-gamma Interferon-gamma IL Interleukin G.P. Nagaraju, S. Ahmad (eds.) Theranostic Approach for Pancreatic Cancer ISBN 978-0-12-819457-7 https://doi.org/10.1016/B978-0-12-819457-7.00005-0
Copyright © 2019 Elsevier Inc. All rights reserved.
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LMPs Latent membrane proteins MDSCs Myeloid-derived suppressor cells MHC-1 Major histocompatibility complex-1 NSCLC Nonesmall cell lung cancer PD-1 Programmed cell death protein-1 PDA Pancreatic ductal adenocarcinoma PD-L1 Programmed cell death protein-ligand STAT3 Signal transducer and activator of transcription TAMs Tumor-associated macrophages Tregs T-regulatory cells
Introduction Cancer cells are resistant to cell death owing to enhanced inflammation in series mutations in proto-oncogenes and oncogenes. Several tumor types also have hallmark cascades, which include the sustainment of proliferative signals, evasion of growth suppressors, avoidance of immune destruction, enabling of replicative immortality, tumor-promoting inflammation, activation of invasion and metastasis, induction of angiogenesis, genome instability and mutations, deregulation of cellular energetics, and resistance to cell death [1,2]. Cancer research has focused on the tumor microenvironment and the complex interaction between it and the tumor. The tumor microenvironment consists of multiple cell types such as vascular endothelium, inflammatory cells, and mesenchymal cells (fibroblasts of various types). In addition to these cells, resident fibroblasts, pericytes, leukocytes, and extracellular matrix components contribute to the development of cancer progression through the tumor microenvironment [3,4]. Ongoing research aims to shed light on the relation between the pancreatic tumor microenvironment and cancer metastasis that pancreatic ductal adenocarcinoma (PDA) develops, depending on the tumor microenvironment [5]. The tumor microenvironment contributes aggressively to the development of tumor progression and metastasis rather than acting as a nonparticipant. Therefore, therapeutic approaches targeting the tumor microenvironment as well as metastasis have great potential. We need to know how the tumor microenvironment works, operates, and functions, with all of its complex interactions (signals, stromal cells, metabolites, etc.) and consequently, how we can make our therapies more effective. To this end, we will discuss the role of the tumor microenvironment in managing tumor development and it relation to cancer immunotherapy.
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Future studies elucidating the mechanisms of the metastasis of pancreatic cancer will provide new therapeutic approaches.
What is the role of the tumor microenvironment in regulating cancer cell metabolism? Neoplastic and stromal cells combine to form a tumor structure. Stromal cells are related to immune system cells, because these cells contain cancer associated with mesenchymal cells, especially fibroblasts, myofibroblasts, endothelial cells, pericytes, and inflammatory cells that influence disease intensity. Cancer or tumor cells and all derived components from normal cells must recruit to a primary tumor site to form the tumor microenvironment [6]. After that recruit, these cells can efficiently secrete stimulatory growth factors, cytokines, and chemokines. On the other hand, activated fibroblasts can be modulated by tumor cells and transformed into microenvironment cancer-associated fibroblasts (CAFs) [7]. Hypoxic conditions trigger the secretion of interleukin-6 (IL-6) and induce much more CAF formation. When CAFs are stimulated, they begin modifying angiogenesis via cell recruits (Table 5.1.) [8]. Another important factor for regulating the recruitment of endothelial cells and metastasis is microRNA synthesis in the tumor microenvironment. Publications imply that the tumor microenvironment supports tumor growth and immunity depression [9]. In tumor progression, chemokines and cytokines, which are activated inflammatory cells (such as macrophages, tumor-associated macrophages [TAMs], and vascular endothelial growth factor), also contribute to tumor mass and flow into the tumor site to promote the type of tumor microenvironment conditions described earlier. Pericytes such as endothelial cells have a role in the tumor microenvironment and induce cancer metastasis. Platelets can release several factors such as chemokines and several growth factors which, when activated, contribute to metastasis. Fig. 5.1 shows that the tumor microenvironment regulates cancer metastasis [10,11].
Tumor immunology for metastatic pancreatic cancer Pancreatic cancer is predicted to be the third leading cancer type after breast cancer in the near future in the United States [12].
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Table 5.1 Microenvironment components in pancreatic cancer. Ingredients Examples
Immune cells
Vasculature Mesenchymal cells Extracellular matrix proteins
Chemokine-interleukin
Natural killer cell Myeloid-derived suppressor cells Neutrophils Tumor-associated macrophages Mast cells T Lymphocytes (primarily regulator) Stromal cell-derived factor-1 Major histocompatibility complex 1 Endothelial cells Pericytes Cancer associated fibroblasts Pancreatic stellate cells (PSCs) Collagens I, III, IV Fibroblast-associated protein Fibronectin Growth factors (hepatocyte growth factor) Hyaluronic acid Laminin MMP-2, MMP-9, MMP-13 Secreted protein acidic and rich in cysteine eosteonectin Trombospondin-1/2 Platelets Transforming growth factor-b Chemokine chemokine motif 2 Macrophage colony-stimulating factor Monocyte chemotactic protein 1 IL-6 IL-10
IL, interleukin; MMP, matrix metalloproteinase.
Conventional treatment of pancreatic cancer is limited to stopping the invasion of tumor cells in the body. Evidence in the field of tumor immunology research has improved our knowledge of how tumor cells circumvent immune surveillance and how tumors directly repress immune progression [13,14]. Because of immune system mechanisms, immunotherapy strategies have been developed to suppress antitumor immunity of the tumor microenvironment and control tumor evasion in the body [15e17].
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Figure 5.1 The tumor microenvironment supports progressive pancreatic cancer metastasis. Emts, epithelial to mesenchymal transitions.
The mechanism of cancer cells has the property of uncontrolled expression. Cancer cells are simply mutated, modified, misfolding proteins. Immune surveillance is the first step to filtrate malignant cells, but tumor cells have developed strategies to escape from the immune elimination system and continue cancer progression [18] (Fig. 5.2). In some patients with cancer, the presence of tumor-associated antigens (TAAs) can be considered evidence of an immune response in many types of pancreatic cancer [19]. Tumor cells express major histocompatibility complex (MHC), which binds peptide from outside and interacts at the cell surface with T cells of the immune system via T-cell antigen receptors. T-cell activation is necessary for this interaction, but not sufficient. However, the signal that effects T-cell activation is dispatched by dendritic cells (DCs), which are the key constituents of the immune response of a cell [20]. Tumor cells can also escape from immune recognition by downregulating antigens such as MHC I pathway proteins or latent membrane
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Figure 5.2 Immunotherapy strategies to overcome tumor cell invasion. Lenf, lymphatic.
proteins (LMP2 and LMP7) [21]. T-cell effectors recognize these tumor antigens (CD8þ or CD4þ T cells) [22]. If these antigens are lacking or genetic stability is lost, cell division is disrupted. After this, tumor cells exhibit unlimited division. There is increasing evidence that the tumor microenvironment of pancreatic cancer is much more suited to immune escape [23].
Immunoediting Studies have shown that patients with pancreatic cancer have an abundance of tumor-reactive T lymphocytes in bone marrow, leukocyte infiltrate, regulatory T cells (Tregs), TAMs, and myeloid-derived suppressor cells (MDSCs) [24e26]. MDSC levels are elevated in both the blood and the tumor microenvironment of patients with pancreatic cancer, which inhibits T-cell activation. Treg cell numbers grow significantly to suppress host immune activity [27,28]. Changes in the immunogenicity of cancer cells that provoke immune resistance are collectively known as tumor immunoediting. In this phase, called the elimination phase, proteins are mutated or modified owing to several attacks on the tumor cell. However, immune surveillance copes with tumor cells via native immune forces [29].
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Immune surveillance of this system forms innate immune cells such as NK, NKT, gd-T, and DCs [30,31]. Native immune cells recognize tumor cells and the battle is partially started by native immune cells. The battle includes several warriors such as tumor antigen-specific T cells CD4þ and CD8þ, which are recruited to the tumorigenesis site to eliminate tumor cells [22,32]. The second phase, equilibrium, is started while elimination of tumor cells continues by immune surveillance. During this period, some tumor cells have increased resistance to the elimination process owing to the mutated tumor cell [33]. These tumor cell variants are associated with a nonimmunogenic phenotype. Therefore, tumor antigens are incapable of downregulating the tumor cell number and epigenetic alterations, accompanied by increased tumorigenesis. This step is the longest process in cancer immunoediting; it will stop when the final phase called escape, begins [34,35]. In this phase, cancer cells are transformed genetically as well as epigenetically, and are inclined to escape from immune surveillance. T-cell antigen expression drops even further, and tumorigenesis may develop more freely owing to extrinsic factors compared with the elimination phase [36]. Tumor cells from the tumor microenvironment stimulate immune system molecules to release immunosuppressive cytokines such as IL-1, IL-6, and IL-10 or induce immune checkpoint molecules such as the B7 family [37,38]. Manipulated tumor cells have increased resistance to apoptosis by overexpression of signal transducer and activator of transcription 3 or B-cell lymphoma 2. The immune escape phase is expanded (Table 5.2) [39].
Development of strategies that target immune checkpoints The immune system is regulated by stimulatory and inhibitory signals. Foreign antigens stimulate immune system cells, especially DCs that manage T-cell induction, to respond to and clear unwanted tumor cells. On the other hand, coinhibitory signals of antitumor response are regulated by the numbers of inhibitory molecules. B7-1 and B7-2 are bound to their receptor (CD28) on T cells to form a costimulatory message. However, they can generate coinhibitory messages when they bind to cytotoxic T lymphocyte antigen-4 (CTLA4) on T cells. The T-cell activation rate and programmed cell death protein I (PD-1) expression are reduced upon coinhibitory signals whereas CTLA4 activation is increased and immune activation is interrupted [40,41].
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Table 5.2 Mechanisms of immune tolerance in pancreatic cancer [24,38]. Processes involved in immune tolerance Regulatory ingredients
Change in cytokines and chemokines regulation
Tolerance persuaded with DC differentiation and regulation
Downregulation of costimulatory signals Immune checkpoints at molecular level
Cellular checkpoints of immune activity
Change metabolism in immune cells
Upregulation of transforming growth factor-b signaling and IL-10 Downregulation of IL-12 and IFN-gamma Release of IL-1, IL-6, IL-10 Naive DCs Upregulation of vascular endothelial growth factor, cyclooxygenase-2, IL-6, and macrophage colony-stimulating factor Downregulation of granulocyte macrophage colony-stimulating factor, IL-4, IL-12, and IFN-gamma Downregulation of B7-1 and B7-2 Presence and/or upregulation of cytotoxic T-lymphocyte antigen-4, PD-L1/B7eH1, PD-L2/B7eH3, B7eH4, programmed cell death protein-1 Overexpression of signal transducer and activator of transcription 3 and B-cell lymphoma 2 Downregulation of Tregs Elevated of myeloid-derived suppressor cell levels Tumor-associated macrophage Upregulation of indoleamine-2,3 dioxygenase, arginase, nitric oxide synthase, etc. Downregulation of MHC 1, major histocompatibility complex 1, LMP2 and LMP7
DCs, dendritic cells; IFN-gamma, interferon-gamma; IL, interleukin; PD-L1, programmed cell death protein-ligand 132 LMP, latent membrane protein family; Treg, T-regulatory cell.
Immune mechanisms are based on immune checkpoint strategies for the treatment of tumor cells. CTLA4 is a key coinhibitory molecule that manages immune regulation. Immunological checkpoints have two important basic goals. First, T-cell activation is generated for self-antigens. Second, when normal T-cell response is increased, another response suppresses foreign pathogens. Tumor cells use this opportunity to evade tissues
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during the suppression phase. All balance is disturbed, and arrows are turned in the direction of coinhibitory signals [42]. Improved immune tolerance is critical for overcoming tumor invasion in patients with pancreatic cancer, with egregious survival rates and poor therapy efficiency. The purpose of the treatment strategy’s is to generate downregulated CTLA4 in tumor invasion, which demonstrates the important role of CTLA4 in tumor immune evasion [43,44]. CTLA4 blocking antibodies are used to improve the rejection of tumors, a technique currently under clinical investigation. There are two antibodies: ipilimumab and tremelimumab. However, CTLA4 monotherapy is supported by generations of antitumor immunity in some tumor models whereas monotherapy is ineffective against mammary tumors and melanoma [45]. Bengsch et al. presented results on pancreatic ductal adenocarcinoma (PDA) mouse models, the most frequent type of pancreatic cancer, blocking CTLA4 to induce T-cell tumor infiltration. However, clinical trials with CTLA4 immunotherapy have failed [46]. Another result is given in a genetically engineered PDA murine model, in which the effects of CTLA4 antibodies against tumor growth have also been unsatisfactory [26]. Contrary to several negative results, a different study showed that induced T-cell-response with CD40 monoclonal antibodies plus gemcitabine and NAB-paclitaxel is highly success in overcoming PDA resistance to CTLA4 immunotherapy [47]. As discussed earlier, T-cells regulate antitumor activity through costimulatory signals such as B7-1/B7-2- and CTLA4, which affect each other and tumor cells and other cells within the tumor microenvironment. PD-11 and its ligand, programmed cell death protein-ligand 1 (PD-L1) (B7/H1) are coinhibitory signals that belong to the B7 family. Overexpression of PDL-1 in cancer is formed after activation of T cells, B cells, and macrophages. Results of PD-L1 activation are accompanied by potent immune suppression and tumor immune escape. PD-1 is also expressed by pancreatic tumor cytotoxic infiltrates [48,49]. Pembrolizumab and nivolumab are both humanized monoclonal antibodies with the aim of blocking human PD-1. Pembrolizumab is approved by the Food and Drug Administration (FDA) to treat PD-L1epositive metastatic nonesmall cell lung cancer (NSCLC) as part of the first- and second-line therapies, and advanced melanoma. Nivolumab is also approved
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by the FDA to treat NSCLC as a second-line therapy for recurrent squamous cell carcinoma of the head and neck [50,51]. These antibodies have lower toxicity compared with anti-CTLA4 antibodies. Therefore, research into PD-1 blockage with tumor vaccines has reached a milestone [52,53]. Tregs maintain a high expression of CD4þCD25þFoxP3þ precursors that prevent autoimmune diseases. However, several studies showed that these cells are recruited to the tumor site and alter antitumor immune response [54,55]. Targeted strategies are not able to increase or decrease Tregs specifically to regulate immune checkpoints in human cancer patients. CD25þ antibodies are used to drain Tregs in human vaccine trials, but these human vaccination strategies employing targeted CD25þ antibodies are inefficient for depleting Tregs. This ineffective result was shown in another clinical trial using a protein that binds CD25þ, called ONTAK [56,57]. In yet another targeting strategy, the basic objective is also to inhibit Tregs by a chemotherapeutic agent, cyclophosphamide, to regulate the immune checkpoint response. Unfortunately, it has failed [58]. Indoleamine-2,33 dioxygenase (IDO) activity is another critical regulator of both tumor cell proliferation and immune cell regulation. Overexpression of IDO supports the tumor microenvironment. All approaches point to the fact that the tumor microenvironment is the medium in which immune tolerance is improved [59]. Overexpression of IDO results in reduced tryptophan levels. Owing to tryptophan metabolism, L-arginine metabolism is also impaired, which renders it unable to contribute positively to the tumor microenvironment. L-Arginine metabolism is regulated by two enzymes, arginase and nitric oxide synthase, both of which are overexpressed. Studies demonstrated the critical role that the two enzymes have in regulating the immune response [60]. This is supported further by evidence that when both arginine and nitric oxide synthase are blocked by a combination of nitroaspirin and sildenafil via a tumor vaccine or adaptive T-cell therapy, the survival rate of tumor-bearing mice improves [61].
Conclusion The immune system has an important role in regulating the tumor microenvironment. Pancreatic cancer exhibits high-intensity downregulation of the immune system whose job is to tag and capture malignant cells.
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Therefore, therapeutic approaches have not yet produced the desired clinical benefit, except for some patients. Tumors and the tumor microenvironment cause disruption of antigenicity and immunogenicity through their ability to establish an immunosuppressive microenvironment. The mechanisms of immune system depression by the tumor microenvironment should be elucidated to enable the conception of new therapeutic approaches. It appears that treatments of metastatic pancreatic cancer based on improving immune tolerance will yield better clinical outcomes. New therapeutic strategies may focus on personalized immune profiling of the tumor microenvironment and mapping their antigenicity and immunogenicity, to distinct benefit.
Conflict statement The authors declare that they have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the chapter.
Acknowledgments This work has not been funded by any financial organization. Murat Köksal (M.Sc. Pharm.) participated in drafting the chapter. Ödül Tetik (B.Sc. Math.) edited the manuscript. Both authors gave final approval of the submitted version.
References [1] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646e74. [2] Hanahan D, Weinberg RA. The Hallmark of cancer. Cell 2000;100:57e70. [3] Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012;12:253e68. [4] Yuan Y, Jiang Y, Sun C, Chen Q. Role of the tumor microenvironment in tumor progression and the clinical applications. Oncology Rep 2016;35:2499e515. [5] Ren B, Cui M, Yang G, Wang H, Feng M, You L, Zhao Y. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer 2018;17:108. [6] Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19:1423e37. [7] Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 2006;5:1597e601. [8] Ko AH. Progress in the treatment of metastatic pancreatic cancer and the search for next opportunities. J Clin Oncol 2015;33(16):1779e86. [9] Png KJ, Halberg N, Yoshida M, Tavazoie SF. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature 2011;481:190e4.
108
Theranostic Approach for Pancreatic Cancer
[10] Coussen LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 2013:286e91. [11] Jeon S-M. Hay Nç Expanding the concepts of cancer metabolism. Exp Mol Med 2018;32:1e3. [12] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7e30. [13] Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Investig 2007;117:1137e46. [14] Chew V, Toh HC, Abastado JP. Immune microenvironment in tumor progression: characteristics and challenges for therapy. J Oncol 2012;2012:608406. [15] Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2014;21:687e92. [16] Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HMCS, Signori E, Honokik K, Georgakilas AG, Amin A, Helferich WG, Boosani CS, Guha G, Ciriolo MR, Chen S, Mohammed SI, Azmi AS, Keith WN, Bilsland A, Bhaktaq D, Halicka D, Fujii H, Aquilanor K, Ashraf SS, Nowsheen S, Yango X, Choiz BK, Kwonaz BS. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015;35:S185e98. [17] Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015;27:450e61. [18] Lowy AM, Leach SD, Philip PA, Pollock RE, editors. Pancreatic cancer. 1st ed. New York: Springer; 2008. [19] Zhang JY, Tan EM. Autoantibodies to tumor-associated antigens as diagnostic biomarkers in hepatocellular carcinoma and other solid tumors. Expert Rev Mol Diagn 2010;10:321e8. [20] Tai Y, Wang Q, Korner H, Zhang L, Wei W. Molecular mechanisms of T cells activation by dendritic cells in autoimmune diseases. Front Pharmacol 2018;9:642. [21] Ferrington DA, Gregerson DS. Immunoproteasomes: structure, function, and antigen presentation. Prog Mol Biol Transl Sci 2012;109:75e112. [22] Hadrup S, Donia M, Thor Straten P. Effector CD4 and CD8 T cells and their role in the tumor microenvironment. Cancer Microenviron 2012;6(2):123e33. [23] Restifo NP, Esquivel F, Kawakami Y, Yewdell JW, Mulé JJ, Rosenberg SA, Bennink JR. Identification of human cancers deficient in antigen processing. J Exp Med 1993;177:265e72. [24] Neoptolemos JP, Urrutia R, Abbruzzese JL, Büchler MW, editors. Pancreatic cancer. 2nd ed. New york: Springer; 2018. [25] Hall M, Liu H, Malafa M, Centeno B, Hodul PJ, Pimiento J, Plion-Thomas S, Samaik AA. Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors. J Immunother Cancer 2016;4:61. [26] Martinez-Bosch N, Vinaixa J, Navarro P. Immune evasion in pancreatic cancer: from mechanisms to therapy. Cancers (Basel) 2018;10(1):6. [27] Xuhao N, Jinhui T, Joseph B, Qian C, Park BV, Zhiguang L, Nailing Z, Andriana L, Anjali R, Ping W, Ying Z, Xuehong Z, Zingmei W, Paolo V, Cui Ping Y, Huabin L, Drew P, Ling L, Duojia PFP. YAP is essential for Treg-mediated suppression of Antitumor I_mmunity. Cancer Discov 2018;8:1026e43. [28] Feng S, Cheng X, Zhang L, Lu X, Chaudhary S, Teng R, Frederickson C, Champion MM, Zhao R, Cheng L, Gong Y, Deng H, Lu X. Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers. Proc Natl Acad Sci USA 2018;115:10094e9. [29] Becker JC, Andersen MH, Schrama D, Thor Straten P. Straten Immune-suppressive properties of the tumor microenvironment. Cancer Immunol Immunother 2013;62:1137e48.
The role of the tumor microenvironment in the metastasis of pancreatic cancer
109
[30] Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, Deng W, Wang L, Shifrin N, Raulet DH. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol 2014;122:91e128. [31] McEwen-Smith RM, Salio M, Cerundolo V. The regulatory role of invariant NKT cells in tumor immunity. Cancer Immunol Res 2015;3:425e35. [32] Kohlgruber AC, Donado CA, Lamarche NM, Brenner MB, Brennan PJ. Activation strategies for invariant natural killer T cells. Immunogenetics 2016;68:649e63. [33] Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011;331:1565e70. [34] Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science 2013;339(6127):1546e58. [35] Chatterjee A, Rodger EJ, Eccles MR. Epigenetic drivers of tumorigenesis and cancer matastasis. Semin Canc Biol 2018;51:149e59. [36] Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007;121(1):1e14. [37] Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577e81. [38] Bekaii-Saab T, El-Rayes B, editors. Current and emerging therapies in pancreatic cancer. eBook. 1st ed. Springer; 2018. [39] Nurieva R, Wang J, Sahoo A. T-cell tolerance in cancer. Immunotherapy 2013;5(5):513e31. [40] Johnson III BA, Yarchoan M, Lee V, Laheru DA, Jaffee EM. Strategies for increasing pancreatic tumor immunogenicity. Clin Cancer Res 2017;23:1656e69. [41] Lippe MJ, Le DT, editors. Pancreatic cancer: a patient and his doctor balance and truth. 1st ed. Baltimore: The John Hopkins University Press; 2011. [42] Wu Y, Zheng Z, Jiang Y, Chess L, Jiang H. The specificity of T cell regulation that enables self-nonself discrimination in the periphery. Proc Natl Acad Sci USA 2009;106:534e9. [43] Noh KH, Kang TH, Kim JH, Pai SI, Lin KY, Hung CF, Wu TC, Kim TW. Activation of Akt as a mechanism for tumor immune evasion. Mol Ther 2008;17:439e47. [44] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012b;366. 2443e54. [45] Callahan MK, Wolchok JD, Allison JP. Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol 2010;37:473e84. [46] Bengsch F, Knoblock DM, Liu A, McAllister F, Beatty GL. CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. Cancer Immunol Immunother 2017;66:1609e17. [47] Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, Clendenin C, Stanger BZ, Furth EE, Wherry EJ, Vonderheide RH. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol Res 2015;3:399e411. [48] Lu C, Paschall AV, Shi H, Savage N, Waller JL, Sabbatini ME, Oberlies NH, Pearce C, Liu K. The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion. J Natl Cancer Inst 2017;109:djw283.
110
Theranostic Approach for Pancreatic Cancer
[49] Munir S, Andersen GH, Ö M, Donia M, Frøsig TM, Larsen SK, Klausen TW, Svane IM, Andersen MH. HLA-restricted CTL that are specific for the immune checkpoint ligand PD-L1 occur with high frequency in cancer patients. Cancer Res 2013;73:1764e76. 15. [50] Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, Keegan P, Pazdur R. FDA approval summary: nivolumab for the treatment of metastatic nonsmall cell lung cancer with progression on or after platinum-based chemotherapy. Oncol 2016;21:634e42. [51] Fessas P, Lee H, Ikemizu S, Janowitz T. A molecular and preclinical comparison of the PD-1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol 2017;44:136e40. [52] Bowyer S, Prithviraj P, Lorigan P, Larkin J, McArthur G, Atkinson V, Khou M, Diem S, Ramanujam S, Kong B, Liniker E, Guminski A, Parente P, Andrews MC, Parakh S, Cebon J, Long GV, Carlino MS, Klein O. Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. Br J Cancer 2016;114:1084e9. [53] Ye Z, Qian Q, Jin H, Qian Q. Cancer vaccine: learning lessons from immune checkpoint inhibitors. J Cancer 2018;9:263e8. [54] Ziani L, Chouaib S, Thiery J. Alteration of the antitumor immune response by cancerassociated fibroblasts. Front Immunol 2018;9:414. [55] Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011;241:260e8. [56] Lansigan F, Stearns DM, Foss F. Role of denileukin diftitox in the treatment of persistent or recurrent cutaneous T-cell lymphoma. Cancer Manag Res 2010;2:53e9. [57] Lutz MB, Baur AS, Schuler-Thurner B, Schuler G. Immunogenic and tolerogenic effects of the chimeric IL-2-diphtheria toxin cytocidal agent Ontak®on CD25þ cells. OncoImmunology 2014;3:e28223. [58] Pitt JM, Vétizou M, Daille`re R, Roberti MP, Yamazaki T, Routy B, Lepage P, Gomperts Boneca I, Chamaillard M, Kroemer G, Zitvogel L. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity 2016;44:1255e69. [59] Devaud C, John LB, Westwood JA, Darcy PK, Kershaw MH. Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy. OncoImmunology 2013;2:e25961. [60] Kim SH, Roszik J, Grimm EA, Ekmekcioglu S. Impact of l-arginine metabolism on immune response and anticancer immunotherapy. Front Oncol 2018;8:67. [61] Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 2006;27:2691e702.