- Email: [email protected]
Firing Up Cold Tumors
TRECAN 00365 No. of Pages 3
Trends in Cancer
Forum
Cancer immunotherapy harnessing patients’ own immune system to eliminate tumors represents a major breakthrough for treating advanced tumors. Among these cancer immunotherapies, immune checkpoint blockade (ICB) treatment, in particular blockade of programmed death-1 (PD-1), which rejuvenates antitumor responses of dysfunctional tumorspecific T cells, yields remarkable clinical benefits. Currently, PD-1/PD-L1 targeting agents are approved by the FDA for cancer therapy in various tumor types, from solid tumor to lymphoma [1]. However, a large proportion of patients are refractory to PD-1/PD-L1 blockade treatment often due to the lack of pre-existing T cell infiltration in tumors, an immune state known as cold tumors. Thus, boosting T cell infiltration into tumors becomes a critical task for improving ICB treatment.
addition, the retention of cDC1 in tumors attracts T cell infiltration into tumors via the production of CXCL9 and CXCL10, which positively associates with stronger therapeutic outcomes of PD-1/PD-L1 blockade in different murine tumor models [3–5]. Hence, cDC1 play a critical role in supporting the engagement of multiple steps of the anticancer immunity cycle; however, it remains a major hurdle to stimulate the recruitment of cDC1 into tumors and drive the maturation of cDC1 for cancer treatment. Recently, oncogenic activation of the β-catenin pathway in melanomas has been revealed to stimulate formation of cold tumors by an activating transcription factor 3 (ATF3)-dependent transcriptional suppression of CCL4, one of the chemokines supporting cDC1 recruitment [6]. Since then, other oncogenic mutations have also been proposed to impact the immune status of the TME via undefined regulations on chemokine production [7]. In addition, the robust production of prostaglandin E2 (PGE2) in tumors has also been reported to prevent cDC1 tumor infiltration [8]. Mechanistically, PGE2 suppresses NK cell-mediated production of cDC1 chemo-attractants, including CCL5 and XCL1, by inducing apoptosis in NK cells infiltrating into the TME. This event in turn leads to declined CD8+ T cell tumor infiltration (Figure 1). These findings uncover the mechanisms by which tumor cells coax the formation of the cold TME and suggest targetable approaches to reprogram the TME. Nevertheless, it remains difficult to reprogram the TME into an immune-supportive condition when those tumors harbor nontargetable oncogenic mutations or have little PGE2 signal.
After taking up dying or dead tumor cells in the tumor microenvironment (TME), mature type I conventional dendritic cells (cDC1) can migrate into the tumordraining lymph nodes where cDC1 present tumor antigen to prime and activate tumor antigen-specific T cells [2]. In
We recently identified that the expression of mitochondria uncoupling protein 2 (UCP2) in melanoma cells positively impacts the cDC1-CD8+ T cell antitumor immunity cycle [9]. Of note, the expression levels of UCP2 in tumors do not associate with classic driver mutations and mutation
Firing Up Cold Tumors Wan-Chen Cheng1,2,* and Ping-Chih Ho1,2,*
Elucidating how tumor-intrinsic pathways regulate T cell infiltration in tumors is crucial for developing new therapeutic strategies for immune checkpoint blockade therapy. Here, we review recent progress on how these pathways orchestrate immune status in tumors and discuss the potential interventions for reprogramming the tumor microenvironment for cancer treatment.
loads in melanomas, suggesting that UCP2 expression in melanoma cells may control antitumor immunity via a neo-antigen burden-independent manner and represents a new target for treating nontargetable melanoma patients. Mechanistically, enhancing expression of UCP2 in melanoma cells stimulates CXCL10 production by activating interferon regulatory factor 5 (IRF5). This process leads to a low-grade increase of tumor-infiltration of CD8+ T cells, which in turns produce CCL5 to attract cDC1. As a consequence of chemokine relay, UCP2 expression in melanoma cells inflames cold tumors by boosting the engagement of the cDC1CD8+ T cell antitumor immune cycle (Figure 1). In this study, rosiglitazone, an agonist of peroxisome proliferatoractivated receptor-γ (PPAR-γ), is found to induce UCP2 expression in melanoma cells. As a result of these actions, combination of rosiglitazone with PD-1 blockade yields remarkable synergistic antitumor responses. These findings reveal a new approach with a distinct mechanism to boost cDC1-CD8+ T cell antitumor immune cycle. Although rosiglitazone is an FDA-approved drug for diabetes, it is prohibited in Europe due to the potential for causing severe adverse cardiovascular toxicity. Thus, future studies aiming to examine the therapeutic activity of rosiglitazone with ICB in human melanoma treatment should carefully adjust the dosage of rosiglitazone for minimizing potential toxicity. Moreover, the TGF-β/SMAD pathway, a common pathway that is upregulated in the TME, has been reported to inhibit UCP2 expression [10]. Hence, it is critical to explore whether targeting the TGF-β pathway can also reprogram the TME in a UCP2-dependent manner. Moreover, it is also interesting to elucidate whether rosiglitazone affects the function of other tumor-infiltrating immune cells. For instance, UCP2 expression level in T cells increases after T cell receptor activation and might be involved in metabolic reprogramming for T cell proliferation and Trends in Cancer, Month 2019, Vol. xx, No. xx
1
Trends in Cancer
Trends in Cancer
Figure 1. Cancer Cell-Intrinsic Signaling Pathways Mediate Type I Conventional Dendritic Cells (cDC1) Recruitment. Left: Non-T cell-inflamed tumor microenvironment (TME). Tumor with active Wnt/β-catenin signaling induces activating transcription factor 3 (ATF3) transcription to suppress CCL4 transcription. Cox1/2-prostaglandin E2 (PGE2) pathway impairs NK cell infiltration, which suppresses CCL5 and XCR1 secretion. The declined cDC1-recruiting chemokine production further hampers CD8+ T cell infiltration and causes a T cell-excluded TME. Right: T cell-inflamed TME. Uncoupling protein 2 (UCP2) induction stimulates interferon regulatory factor 5 (IRF5)-dependent CXCL10 production and promotes low-grade CD8+ T cell infiltration. In turn, infiltrating CD8+ T cells produce CCL5 to amplify the cDC1-CD8+ T cell-dependent antitumor immune cycle.
fine-tuning reactive oxygen species (ROS) level to inhibit apoptosis [11]. In contrast, UCP2-deficient macrophages acquire proinflammatory function due to the enhancement of ROS production [12]. Therefore, future works on elucidating the role of UCP2 in immune cells are also warranted for exploiting UCP2-targeting interventions for cancer treatment.
signals impact cDC1-CD8+ T cell antitumor immune cycle, it is likely that a combined parameter evaluating β-catenin signal, PGE2 production, and UCP2 expression in melanoma cells can be a potential biomarker to predict the response of ICB. In addition to enhancing cDC1 infiltration into tumors, facilitating proper maturation of cDC1 is another hurdle for exploiting cDC1-induced antitumor immune responses. Type I interIdentifying reliable biomarkers is essential feron signal induced by ligands of Tollto categorize patients who can benefit like receptor 3, CpG, and STING agonists from PD-1 blockade therapy. Based on has been revealed to play a critical role in recent progresses on how tumor intrinsic supporting cDC1 maturation and cDC12
Trends in Cancer, Month 2019, Vol. xx, No. xx
dependent antitumor responses [13]. However, the systemic engagement of type I interferon signal may result in deleterious side effects. Thus, delivering treatments to specifically induce type I interferon activity in cDC1 becomes an attractive approach, which is under intensive investigations. Importantly, it has also been shown that type I interferoninduced cDC1 maturation suppresses phagocytosis ability of cDC1. This action may compromise the cross-presentation ability of cDC1 if these cDC1 have not obtained tumor antigens [14]. Therefore, treatments that can achieve spatial and
Trends in Cancer
timely activation of type I interferon signal European Research Council (ERC Starting Grant may be used in combination with inter- Agreement number 802773-MitoGuide) to P-C.H. ventions facilitating cDC1 tumor infiltration to maximize cold → hot conversion Disclaimer Statement P-C.H. has received research supports from Roche in the TME.
4.
5.
and Idorsia. P-C.H. is also a member of the scientific
Altogether, understanding how tumorintrinsic pathways mediate the immune cell composition, especially cDC1, is important to develop next-generation immunotherapies against cancer. Emerging findings provide both negative and positive regulatory circuits centering on cDC1 recruitment and the determination of immune status in tumors. Exploiting these mechanisms may lead to development of a new generation of immunotherapy for overcoming the primary resistance to PD-1 blockade therapy. Acknowledgments This study was supported in part by the SNSF project grant (31003A_182470 and 31003A_163204), CLIP award from the Cancer Research Institute, and
advisory board of Elixiron Immunotherapeutics.
6. 7.
1
Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland 2 Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland *Correspondence: [email protected] (W.-C. Cheng) and [email protected] (P.-C. Ho).
8.
9.
10.
https://doi.org/10.1016/j.trecan.2019.06.005 11. © 2019 Elsevier Inc. All rights reserved.
References 1. Ribas, A. and Wolchok, J.D. (2018) Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 2. Roberts, E.W. et al. (2016) Critical role for CD103(+)/ CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 3. Salmon, H. et al. (2016) Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site
12.
13.
14.
enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 Spranger, S. et al. (2017) Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723 Sanchez-Paulete, A.R. et al. (2016) Cancer immunotherapy with immunomodulatory anti-CD137 and antiPD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov. 6, 71–79 Spranger, S. et al. (2015) Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 Spranger, S. and Gajewski, T.F. (2018) Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 Bottcher, J.P. et al. (2018) NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 Cheng, W.C. et al. (2019) Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle. Nat. Immunol. 20, 206–217 Sayeed, A. et al. (2010) Negative regulation of UCP2 by TGFbeta signaling characterizes low and intermediategrade primary breast cancer. Cell Death Dis. 1, e53 Rupprecht, A. et al. (2012) Quantification of uncoupling protein 2 reveals its main expression in immune cells and selective up-regulation during T-cell proliferation. PLoS One 7, e41406 Arsenijevic, D. et al. (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat. Genet. 26, 435–439 Sanchez-Paulete, A.R. et al. (2017) Antigen crosspresentation and T-cell cross-priming in cancer immunology and immunotherapy. Ann. Oncol. 28, xii74 Tzeng, A. et al. (2016) Temporally programmed CD8alpha(+) DC activation enhances combination cancer immunotherapy. Cell Rep. 17, 2503–2511
Trends in Cancer, Month 2019, Vol. xx, No. xx
3
Trends in Cancer
Forum
Cancer immunotherapy harnessing patients’ own immune system to eliminate tumors represents a major breakthrough for treating advanced tumors. Among these cancer immunotherapies, immune checkpoint blockade (ICB) treatment, in particular blockade of programmed death-1 (PD-1), which rejuvenates antitumor responses of dysfunctional tumorspecific T cells, yields remarkable clinical benefits. Currently, PD-1/PD-L1 targeting agents are approved by the FDA for cancer therapy in various tumor types, from solid tumor to lymphoma [1]. However, a large proportion of patients are refractory to PD-1/PD-L1 blockade treatment often due to the lack of pre-existing T cell infiltration in tumors, an immune state known as cold tumors. Thus, boosting T cell infiltration into tumors becomes a critical task for improving ICB treatment.
addition, the retention of cDC1 in tumors attracts T cell infiltration into tumors via the production of CXCL9 and CXCL10, which positively associates with stronger therapeutic outcomes of PD-1/PD-L1 blockade in different murine tumor models [3–5]. Hence, cDC1 play a critical role in supporting the engagement of multiple steps of the anticancer immunity cycle; however, it remains a major hurdle to stimulate the recruitment of cDC1 into tumors and drive the maturation of cDC1 for cancer treatment. Recently, oncogenic activation of the β-catenin pathway in melanomas has been revealed to stimulate formation of cold tumors by an activating transcription factor 3 (ATF3)-dependent transcriptional suppression of CCL4, one of the chemokines supporting cDC1 recruitment [6]. Since then, other oncogenic mutations have also been proposed to impact the immune status of the TME via undefined regulations on chemokine production [7]. In addition, the robust production of prostaglandin E2 (PGE2) in tumors has also been reported to prevent cDC1 tumor infiltration [8]. Mechanistically, PGE2 suppresses NK cell-mediated production of cDC1 chemo-attractants, including CCL5 and XCL1, by inducing apoptosis in NK cells infiltrating into the TME. This event in turn leads to declined CD8+ T cell tumor infiltration (Figure 1). These findings uncover the mechanisms by which tumor cells coax the formation of the cold TME and suggest targetable approaches to reprogram the TME. Nevertheless, it remains difficult to reprogram the TME into an immune-supportive condition when those tumors harbor nontargetable oncogenic mutations or have little PGE2 signal.
After taking up dying or dead tumor cells in the tumor microenvironment (TME), mature type I conventional dendritic cells (cDC1) can migrate into the tumordraining lymph nodes where cDC1 present tumor antigen to prime and activate tumor antigen-specific T cells [2]. In
We recently identified that the expression of mitochondria uncoupling protein 2 (UCP2) in melanoma cells positively impacts the cDC1-CD8+ T cell antitumor immunity cycle [9]. Of note, the expression levels of UCP2 in tumors do not associate with classic driver mutations and mutation
Firing Up Cold Tumors Wan-Chen Cheng1,2,* and Ping-Chih Ho1,2,*
Elucidating how tumor-intrinsic pathways regulate T cell infiltration in tumors is crucial for developing new therapeutic strategies for immune checkpoint blockade therapy. Here, we review recent progress on how these pathways orchestrate immune status in tumors and discuss the potential interventions for reprogramming the tumor microenvironment for cancer treatment.
loads in melanomas, suggesting that UCP2 expression in melanoma cells may control antitumor immunity via a neo-antigen burden-independent manner and represents a new target for treating nontargetable melanoma patients. Mechanistically, enhancing expression of UCP2 in melanoma cells stimulates CXCL10 production by activating interferon regulatory factor 5 (IRF5). This process leads to a low-grade increase of tumor-infiltration of CD8+ T cells, which in turns produce CCL5 to attract cDC1. As a consequence of chemokine relay, UCP2 expression in melanoma cells inflames cold tumors by boosting the engagement of the cDC1CD8+ T cell antitumor immune cycle (Figure 1). In this study, rosiglitazone, an agonist of peroxisome proliferatoractivated receptor-γ (PPAR-γ), is found to induce UCP2 expression in melanoma cells. As a result of these actions, combination of rosiglitazone with PD-1 blockade yields remarkable synergistic antitumor responses. These findings reveal a new approach with a distinct mechanism to boost cDC1-CD8+ T cell antitumor immune cycle. Although rosiglitazone is an FDA-approved drug for diabetes, it is prohibited in Europe due to the potential for causing severe adverse cardiovascular toxicity. Thus, future studies aiming to examine the therapeutic activity of rosiglitazone with ICB in human melanoma treatment should carefully adjust the dosage of rosiglitazone for minimizing potential toxicity. Moreover, the TGF-β/SMAD pathway, a common pathway that is upregulated in the TME, has been reported to inhibit UCP2 expression [10]. Hence, it is critical to explore whether targeting the TGF-β pathway can also reprogram the TME in a UCP2-dependent manner. Moreover, it is also interesting to elucidate whether rosiglitazone affects the function of other tumor-infiltrating immune cells. For instance, UCP2 expression level in T cells increases after T cell receptor activation and might be involved in metabolic reprogramming for T cell proliferation and Trends in Cancer, Month 2019, Vol. xx, No. xx
1
Trends in Cancer
Trends in Cancer
Figure 1. Cancer Cell-Intrinsic Signaling Pathways Mediate Type I Conventional Dendritic Cells (cDC1) Recruitment. Left: Non-T cell-inflamed tumor microenvironment (TME). Tumor with active Wnt/β-catenin signaling induces activating transcription factor 3 (ATF3) transcription to suppress CCL4 transcription. Cox1/2-prostaglandin E2 (PGE2) pathway impairs NK cell infiltration, which suppresses CCL5 and XCR1 secretion. The declined cDC1-recruiting chemokine production further hampers CD8+ T cell infiltration and causes a T cell-excluded TME. Right: T cell-inflamed TME. Uncoupling protein 2 (UCP2) induction stimulates interferon regulatory factor 5 (IRF5)-dependent CXCL10 production and promotes low-grade CD8+ T cell infiltration. In turn, infiltrating CD8+ T cells produce CCL5 to amplify the cDC1-CD8+ T cell-dependent antitumor immune cycle.
fine-tuning reactive oxygen species (ROS) level to inhibit apoptosis [11]. In contrast, UCP2-deficient macrophages acquire proinflammatory function due to the enhancement of ROS production [12]. Therefore, future works on elucidating the role of UCP2 in immune cells are also warranted for exploiting UCP2-targeting interventions for cancer treatment.
signals impact cDC1-CD8+ T cell antitumor immune cycle, it is likely that a combined parameter evaluating β-catenin signal, PGE2 production, and UCP2 expression in melanoma cells can be a potential biomarker to predict the response of ICB. In addition to enhancing cDC1 infiltration into tumors, facilitating proper maturation of cDC1 is another hurdle for exploiting cDC1-induced antitumor immune responses. Type I interIdentifying reliable biomarkers is essential feron signal induced by ligands of Tollto categorize patients who can benefit like receptor 3, CpG, and STING agonists from PD-1 blockade therapy. Based on has been revealed to play a critical role in recent progresses on how tumor intrinsic supporting cDC1 maturation and cDC12
Trends in Cancer, Month 2019, Vol. xx, No. xx
dependent antitumor responses [13]. However, the systemic engagement of type I interferon signal may result in deleterious side effects. Thus, delivering treatments to specifically induce type I interferon activity in cDC1 becomes an attractive approach, which is under intensive investigations. Importantly, it has also been shown that type I interferoninduced cDC1 maturation suppresses phagocytosis ability of cDC1. This action may compromise the cross-presentation ability of cDC1 if these cDC1 have not obtained tumor antigens [14]. Therefore, treatments that can achieve spatial and
Trends in Cancer
timely activation of type I interferon signal European Research Council (ERC Starting Grant may be used in combination with inter- Agreement number 802773-MitoGuide) to P-C.H. ventions facilitating cDC1 tumor infiltration to maximize cold → hot conversion Disclaimer Statement P-C.H. has received research supports from Roche in the TME.
4.
5.
and Idorsia. P-C.H. is also a member of the scientific
Altogether, understanding how tumorintrinsic pathways mediate the immune cell composition, especially cDC1, is important to develop next-generation immunotherapies against cancer. Emerging findings provide both negative and positive regulatory circuits centering on cDC1 recruitment and the determination of immune status in tumors. Exploiting these mechanisms may lead to development of a new generation of immunotherapy for overcoming the primary resistance to PD-1 blockade therapy. Acknowledgments This study was supported in part by the SNSF project grant (31003A_182470 and 31003A_163204), CLIP award from the Cancer Research Institute, and
advisory board of Elixiron Immunotherapeutics.
6. 7.
1
Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland 2 Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland *Correspondence: [email protected] (W.-C. Cheng) and [email protected] (P.-C. Ho).
8.
9.
10.
https://doi.org/10.1016/j.trecan.2019.06.005 11. © 2019 Elsevier Inc. All rights reserved.
References 1. Ribas, A. and Wolchok, J.D. (2018) Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 2. Roberts, E.W. et al. (2016) Critical role for CD103(+)/ CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 3. Salmon, H. et al. (2016) Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site
12.
13.
14.
enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 Spranger, S. et al. (2017) Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723 Sanchez-Paulete, A.R. et al. (2016) Cancer immunotherapy with immunomodulatory anti-CD137 and antiPD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov. 6, 71–79 Spranger, S. et al. (2015) Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 Spranger, S. and Gajewski, T.F. (2018) Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 Bottcher, J.P. et al. (2018) NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 Cheng, W.C. et al. (2019) Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle. Nat. Immunol. 20, 206–217 Sayeed, A. et al. (2010) Negative regulation of UCP2 by TGFbeta signaling characterizes low and intermediategrade primary breast cancer. Cell Death Dis. 1, e53 Rupprecht, A. et al. (2012) Quantification of uncoupling protein 2 reveals its main expression in immune cells and selective up-regulation during T-cell proliferation. PLoS One 7, e41406 Arsenijevic, D. et al. (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat. Genet. 26, 435–439 Sanchez-Paulete, A.R. et al. (2017) Antigen crosspresentation and T-cell cross-priming in cancer immunology and immunotherapy. Ann. Oncol. 28, xii74 Tzeng, A. et al. (2016) Temporally programmed CD8alpha(+) DC activation enhances combination cancer immunotherapy. Cell Rep. 17, 2503–2511
Trends in Cancer, Month 2019, Vol. xx, No. xx
3