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Exosomes in immunity and cancer—Friends or foes?
Seminars in Cancer Biology 28 (2014) 1–2
Contents lists available at ScienceDirect
Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer
Editorial
Exosomes in immunity and cancer—Friends or foes?
Extracellular vesicles (EV) have emerged as important means of cell communication, with the capacity to transfer proteins, pathogens and genetic material between cells. EVs are usually divided into microvesicles (MV), originating from the plasma membrane, 100 nm–1 mm in size, and exosomes (exo), deriving from the endosomal compartment, usually described to be 30–120 nm in diameter [1]. This issue focuses on exosomes in relation to cancer, since they are potential disease biomarkers and since they can be exploited as therapeutic tools. The number of publications regarding exosomes has grown exponentially in the last two decades, especially after the finding that exosomes contain mRNA and miRNA [2]. Due to specific sorting mechanisms, not fully elucidated yet, certain molecules are enriched in exosomes compared to their donor cells, while others are absent. What is known about the sorting mechanisms are explained in detail in the present review by Villarroya-Beltri et al. [3]. Exosomes are in addition important players in diverse mechanisms unrelated to cancer such as transfer of HIV, mediation of oral tolerance, successful pregnancy as well as mediators of allergy. In the cancer field, two major functions have emerged, the promotion of cancerous spread by tumor-derived exosomes [4], and induction or enforcement of anti-cancerous immune responses by antigen-presentig cell (APC)-derived exosomes [5]. Tumor-derived exosomes have been shown to promote cancer and metastasis development in several ways. They can inhibit anti-cancer-immune responses, induce angiogenesis and can prepare the pre-metastatic niche to facilitate cancer cell spreading. The review in this issue by Redzic et al. [6] describes the role of exosomal (ex)RNA in disease progression, as well as how these exRNAs could be used as cancer detection markers. This information, as described by the authors, could also be used as therapeutics either by strategies inhibiting specific RNA:s in exosomes, or to administer therapeutic exRNA. Proteins, in or on the surface of exosomes, can have major effects. As Mincheva-Nilsson and Baranov [7] explain in this issue, NKG2D-ligand expressing exosomes can function as decoys to impair cytotoxic functions of NK-NKT, gamma/delta and cytotoxic T cells. However, as mentioned in the article, not much is known about how the expression of the different ligands is regulated, which is desirable in the search for a way to block the expression of these ligands on exosomes. Alternatively, more general mechanisms for exosome production as well as uptake, could be targeted as described by Christianson et al. [8]. Further understanding of
http://dx.doi.org/10.1016/j.semcancer.2014.06.007 1044-579X/© 2014 Published by Elsevier Ltd.
these mechanisms will aid in the development of therapies, which are targeting exosome production or uptake. In another approach, suggested by Thuma and Zöller [9], tumor-derived exosomes could be outcompeted or “outsmarted” by non-transformed exosomes. Furthermore, exosomes from different sources can carry diverse pro-inflammatory molecules, e.g. exosomes from bronchoalveolar lavage fluid from patients with lung diseases induce cytokine production in recipient cells to a higher degree than those from healthy individuals [10]. Altevogt et al. [11] here present the notion that also cancer-derived exosomes might induce a low-grade inflammation, which could either lead to anti-tumor responses or depending on the context, contribute to metastatic spread. Cancer immunotherapy, harnessing the immune system to battle tumors, was voted the breakthrough of last year [12]. B cell and dendritic cell derived exosomes have been exploited in cancer immunotherapy for some time [5,13], even tested in human clinical trials [14,15]. Gehrmann et al. [16] review the mechanisms for how exosomes can stimulate several cells of the immune system. The capability of exosomes to induce both the innate and adaptive arms of the immune system is raising hopes that engineered exosomes might be further optimized to induce long-lasting and strong immune responses. And, the answer to the question “friends or foes?” The research of the next decade will teach us more about the mechanisms of production, uptake and action of exosomes. As the reviews in this issue illustrate, we are steadily coming closer to new therapeutic opportunities where we will enforce the good exosomes and remove the bad ones, increasing the chance of survival in cancer patients. References [1] Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183:1161–72. [2] Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosomemediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654–9. [3] Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, Sánchez-Madrid F, Mittelbrunn M. Sorting it out: regulation of exosome loading. Sem Cancer Biol. [4] Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012;18:883–91. [5] Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cellderived exosomes. Nat Med 1998;4:594–600. [6] Redzic JS, Balaj L, van der Vos KE, Breakefield XO. Extracellular RNA mediates and marks cancer progression. Sem Cancer Biol.
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Editorial / Seminars in Cancer Biology 28 (2014) 1–2
[7] Mincheva-Nilsson L, Baranov V. Cancer exosomes and NKG2D receptor–ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Sem Cancer Biol. [8] Christianson HC, Svensson KJ, Belting M. Exosome and microvesicle mediated phene transfer in mammalian cells. Sem Cancer Biol. [9] Thuma F, Zöller M. Outsmart tumor exosomes to steal the cancer initiating cell its niche. Sem Cancer Biol. [10] Qazi KR, Torregrosa Paredes P, Dahlberg B, Grunewald J, Eklund A, Gabrielsson S. Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis. Thorax 2010;65:1016–24. [11] Altevogt P, Bretz NP, Ridinger J, Utikal J, Umansky V. Novel insights into exosome-induced, tumor-associated inflammation and immunomodulation. Sem Cancer Biol. [12] Couzin-Frankel J. Cancer immunotherapy. Science 2013;342:1432–3. [13] Amigorena S. Anti-tumour immunotherapy using dendritic-cell-derived exosomes. Res Immunol 1998;149:661–2. [14] Escudier B, Dorval T, Chaput N, Andre F, Caby MP, Novault S, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J Transl Med 2005; 3:10.
[15] Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 2005;3:9. [16] Gehrmann U, Näslund TI, Hiltbrunner S, Larssen P, Gabrielsson S. Harnessing the exosome-induced immune response for cancer immunotherapy. Sem. Cancer Biol.
Susanne Gabrielsson ∗ Annika Scheynius Translational Immunology Unit, Department of Medicine, Solna, Karolinska Institutet and University Hospital, SE-176 76 Stockholm, Sweden ∗ Corresponding author. E-mail addresses: [email protected] (S. Gabrielsson), [email protected] (A. Scheynius).
Contents lists available at ScienceDirect
Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer
Editorial
Exosomes in immunity and cancer—Friends or foes?
Extracellular vesicles (EV) have emerged as important means of cell communication, with the capacity to transfer proteins, pathogens and genetic material between cells. EVs are usually divided into microvesicles (MV), originating from the plasma membrane, 100 nm–1 mm in size, and exosomes (exo), deriving from the endosomal compartment, usually described to be 30–120 nm in diameter [1]. This issue focuses on exosomes in relation to cancer, since they are potential disease biomarkers and since they can be exploited as therapeutic tools. The number of publications regarding exosomes has grown exponentially in the last two decades, especially after the finding that exosomes contain mRNA and miRNA [2]. Due to specific sorting mechanisms, not fully elucidated yet, certain molecules are enriched in exosomes compared to their donor cells, while others are absent. What is known about the sorting mechanisms are explained in detail in the present review by Villarroya-Beltri et al. [3]. Exosomes are in addition important players in diverse mechanisms unrelated to cancer such as transfer of HIV, mediation of oral tolerance, successful pregnancy as well as mediators of allergy. In the cancer field, two major functions have emerged, the promotion of cancerous spread by tumor-derived exosomes [4], and induction or enforcement of anti-cancerous immune responses by antigen-presentig cell (APC)-derived exosomes [5]. Tumor-derived exosomes have been shown to promote cancer and metastasis development in several ways. They can inhibit anti-cancer-immune responses, induce angiogenesis and can prepare the pre-metastatic niche to facilitate cancer cell spreading. The review in this issue by Redzic et al. [6] describes the role of exosomal (ex)RNA in disease progression, as well as how these exRNAs could be used as cancer detection markers. This information, as described by the authors, could also be used as therapeutics either by strategies inhibiting specific RNA:s in exosomes, or to administer therapeutic exRNA. Proteins, in or on the surface of exosomes, can have major effects. As Mincheva-Nilsson and Baranov [7] explain in this issue, NKG2D-ligand expressing exosomes can function as decoys to impair cytotoxic functions of NK-NKT, gamma/delta and cytotoxic T cells. However, as mentioned in the article, not much is known about how the expression of the different ligands is regulated, which is desirable in the search for a way to block the expression of these ligands on exosomes. Alternatively, more general mechanisms for exosome production as well as uptake, could be targeted as described by Christianson et al. [8]. Further understanding of
http://dx.doi.org/10.1016/j.semcancer.2014.06.007 1044-579X/© 2014 Published by Elsevier Ltd.
these mechanisms will aid in the development of therapies, which are targeting exosome production or uptake. In another approach, suggested by Thuma and Zöller [9], tumor-derived exosomes could be outcompeted or “outsmarted” by non-transformed exosomes. Furthermore, exosomes from different sources can carry diverse pro-inflammatory molecules, e.g. exosomes from bronchoalveolar lavage fluid from patients with lung diseases induce cytokine production in recipient cells to a higher degree than those from healthy individuals [10]. Altevogt et al. [11] here present the notion that also cancer-derived exosomes might induce a low-grade inflammation, which could either lead to anti-tumor responses or depending on the context, contribute to metastatic spread. Cancer immunotherapy, harnessing the immune system to battle tumors, was voted the breakthrough of last year [12]. B cell and dendritic cell derived exosomes have been exploited in cancer immunotherapy for some time [5,13], even tested in human clinical trials [14,15]. Gehrmann et al. [16] review the mechanisms for how exosomes can stimulate several cells of the immune system. The capability of exosomes to induce both the innate and adaptive arms of the immune system is raising hopes that engineered exosomes might be further optimized to induce long-lasting and strong immune responses. And, the answer to the question “friends or foes?” The research of the next decade will teach us more about the mechanisms of production, uptake and action of exosomes. As the reviews in this issue illustrate, we are steadily coming closer to new therapeutic opportunities where we will enforce the good exosomes and remove the bad ones, increasing the chance of survival in cancer patients. References [1] Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183:1161–72. [2] Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosomemediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654–9. [3] Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, Sánchez-Madrid F, Mittelbrunn M. Sorting it out: regulation of exosome loading. Sem Cancer Biol. [4] Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012;18:883–91. [5] Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cellderived exosomes. Nat Med 1998;4:594–600. [6] Redzic JS, Balaj L, van der Vos KE, Breakefield XO. Extracellular RNA mediates and marks cancer progression. Sem Cancer Biol.
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Editorial / Seminars in Cancer Biology 28 (2014) 1–2
[7] Mincheva-Nilsson L, Baranov V. Cancer exosomes and NKG2D receptor–ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Sem Cancer Biol. [8] Christianson HC, Svensson KJ, Belting M. Exosome and microvesicle mediated phene transfer in mammalian cells. Sem Cancer Biol. [9] Thuma F, Zöller M. Outsmart tumor exosomes to steal the cancer initiating cell its niche. Sem Cancer Biol. [10] Qazi KR, Torregrosa Paredes P, Dahlberg B, Grunewald J, Eklund A, Gabrielsson S. Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis. Thorax 2010;65:1016–24. [11] Altevogt P, Bretz NP, Ridinger J, Utikal J, Umansky V. Novel insights into exosome-induced, tumor-associated inflammation and immunomodulation. Sem Cancer Biol. [12] Couzin-Frankel J. Cancer immunotherapy. Science 2013;342:1432–3. [13] Amigorena S. Anti-tumour immunotherapy using dendritic-cell-derived exosomes. Res Immunol 1998;149:661–2. [14] Escudier B, Dorval T, Chaput N, Andre F, Caby MP, Novault S, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J Transl Med 2005; 3:10.
[15] Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 2005;3:9. [16] Gehrmann U, Näslund TI, Hiltbrunner S, Larssen P, Gabrielsson S. Harnessing the exosome-induced immune response for cancer immunotherapy. Sem. Cancer Biol.
Susanne Gabrielsson ∗ Annika Scheynius Translational Immunology Unit, Department of Medicine, Solna, Karolinska Institutet and University Hospital, SE-176 76 Stockholm, Sweden ∗ Corresponding author. E-mail addresses: [email protected] (S. Gabrielsson), [email protected] (A. Scheynius).