Extracellular Vesicles and Tumor-Immune Escape: Comparison
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The modulation of the immune system is one of the hallmarks of cancer. It is now widely described that cancer cells are able to evade the immune response and thus establish immune tolerance. The exploration of the mechanisms underlying this ability of cancer cells has always attracted the scientific community and is the basis for the development of new promising cancer therapies. Recent evidence has highlighted how extracellular vesicles (EVs) represent a mechanism by which cancer cells promote immune escape by inducing phenotypic changes on different immune cell populations. In this review, we will discuss the recent findings on the role of tumor-derived extracellular vesicles (TEVs) in regulating immune checkpoints, focusing on the PD-L1/PD-1 axis.

  • extracellular vesicles (EVs)
  • cancer immune tolerance
  • immune checkpoints
  • PD-1/PD-L1 axis

Tumors adopt numerous strategies to manipulate the surrounding microenvironment to guarantee and support their development. One of the more powerful strategies through which cancer cells protect their growth concerns the possibility to evade the immune system. Within tumor microenvironment (TME) several mechanisms have been described to be responsible for immune tolerance, ultimately promoting tumor proliferation and metastasis. Cancer cells can induce immune cell death via the FasL/Fas and PD-L1/PD-1 pathways, resulting in a decrease in the number of T-cells and NK cells. In addition, they also recruit the immuno-suppressive Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) that inhibit CD8+ T-cells, resulting in tumor immune escape.

To deeply investigate how cancer cells can activate these immune escape mechanisms, in recent years researchers have focused on the study of extracellular vesicles (EVs), a heterogeneous group of lipoproteic structures, released from all cell types

[1][2]. It has now been widely demonstrated that EVs derived from tumor cells (TEVs) can promote tumor-mediated immune suppression creating a tumor-friendly microenvironment

. It has now been widely demonstrated that EVs derived from tumor cells (TEVs) can promote tumor-mediated immune suppression creating a tumor-friendly microenvironment [3][4]. Many studies are specifically focused on small extracellular vesicles (sEVs), to date also named exosomes, a well-characterized subtype of EVs playing a pleiotropic role in different key processes of tumor formation and progression; in fact, EVs are involved in tumor microenvironment (TME) remodeling as angiogenesis [5][6][37], invasion

[48]. Many studies are specifically focused on small extracellular vesicles (sEVs), to date also named exosomes, a well-characterized subtype of EVs playing a pleiotropic role in different key processes of tumor formation and progression; in fact, EVs are involved in tumor microenvironment (TME) remodeling as angiogenesis [59]

, metastasis

[610][711], invasion

, and resistance to therapies

[812][913], metastasis

. sEVsare nano-sized (40–100 nm) membrane-delimited vesicles that are secreted by almost all cell types under both normal and pathological conditions. They are usually detected in biological fluids like blood, urine, ascitic fluid and others. sEVs transport various biomolecules, such as proteins, messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs)

[102][113], and resistance to therapies

; common exosomal markers include HSp70, CD9, CD63, and CD81

[124][135]. sEVsare nano-sized (40–100 nm) membrane-delimited vesicles that are secreted by almost all cell types under both normal and pathological conditions. They are usually detected in biological fluids like blood, urine, ascitic fluid and others. sEVs transport various biomolecules, such as proteins, messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) [2,3]; common exosomal markers include HSp70, CD9, CD63, and CD81 [4,5]. The release of sEVs is a complex process that the cells execute following multiple steps in which different proteins are involved. Among those, neutral sphingomyelinase 2 (nSMase2)

. The release of sEVs is a complex process that the cells execute following multiple steps in which different proteins are involved. Among those, neutral sphingomyelinase 2 (nSMase2)

[14]

, phosphorylated synaptosome-associated protein 23 (SNAP23) 

[15][16] and Ras-related RAB proteins (RAB27A/RAB27B)

 and Ras-related RAB proteins (RAB27A/RAB27B)

[17][18]

regulate sEV secretion from different cancer cells like breast cancer

[14]

, hepatocellular carcinoma (HCC)

[15][16]

, and colorectal cancer

[18]

.

In the next sections, we will discuss the scientific evidence showing that EVs and in particular sEVs released by cancer cells play a key role in promoting the immune escape of the tumor, specifically modulating the behavior of each cellular component of tumor immune microenvironment. Particular emphasis will be given to the role that tumor-derived extracellular vesicles (TEVs) have in regulating immune checkpoint directly activating the PD-L1/PD-1 axis.

In conclusion, here we reported the evidence of the involvement of TEVs as contributors to the cancer-immune escape, highlighting their role in modulating the PD-L1/PD-1 axis. The studies discussed above suggest that the development of EV targeting strategies can improve anti-cancer immunotherapies. Some approaches are conceivable and part of the scientific community in the field is focused on these; for example, inhibiting the release of vesicles by cancer cells, or blocking their specific interaction with target cells is under investigation. However, although promising, the detailed examination of vesicle content, combined with the in-depth comprehension of the in vivo mechanisms underlying TEV-mediated immune escape, are necessary steps for the further clinical application.
 

In conclusion, here we reported the evidence of the involvement of TEVs as contributors to the cancer-immune escape, highlighting their role in modulating the PD-L1/PD-1 axis. The studies discussed above suggest that the development of EV targeting strategies can improve anti-cancer immunotherapies. Some approaches are conceivable and part of the scientific community in the field is focused on these; for example, inhibiting the release of vesicles by cancer cells, or blocking their specific interaction with target cells is under investigation. However, although promising, the detailed examination of vesicle content, combined with the in-depth comprehension of the in vivo mechanisms underlying TEV-mediated immune escape, are necessary steps for the further clinical application.

References

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  13. Mirjam C. Boelens; Tony James Wu; Barzin Y. Nabet; Bihui Xu; Yu Qiu; Taewon Yoon; Diana Azzam; Christina Twyman-Saint Victor; Brianne Z. Wiemann; Hemant Ishwaran; et al.Petra J. Ter BruggeJos JonkersJoyce SlingerlandAndy J. Minn Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.. Chi Lam Au Yeung; Ngai-Na Co; Tetsushi Tsuruga; Tsz-Lun Yeung; Suet Ying Kwan; Cecilia S. Leung; Yong Li; Edward S. Lu; Kenny Kwan; Kwong Kwok Wong; Rosemarie Schmandt; Karen H. Lu; Samuel C. Mok; Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nature Cell ommunications 2014, 159, 499-513, 10.1016/j.cell.2014.09.051.6, 7, 11150, 10.1038/ncomms11150.
  14. Kerstin Menck; Can Sönmezer; Thomas Stefan Worst; Matthias Schulz; Gry Helene Dihazi; Frank Streit; G. Erdmann; Simon Kling; Michael Boutros; Claudia Binder; et al.Julia Christina Gross Neutral sphingomyelinases control extracellular vesicles budding from the plasma membrane. Journal of ExtracMirjam C. Boelens; Tony James Wu; Barzin Y. Nabet; Bihui Xu; Yu Qiu; Taewon Yoon; Diana Azzam; Christina Twyman-Saint Victor; Brianne Z. Wiemann; Hemant Ishwaran; Petra J. Ter Brugge; Jos Jonkers; Joyce Slingerland; Andy J. Minn; Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.. Cellular Vesicles 2017, 6, 1378056, 10.1080/20013078.2017.1378056.4, 159, 499-513, 10.1016/j.cell.2014.09.051.
  15. Yao Wei; Ng Wang; Fangfang Jin; Zhen Bian; Limin Li; Hongwei Liang; Mingzhen Li; Lei Shi; Chaoyun Pan; Dihan Zhu; et al.Xi ChenGang HuYuan LiuChen Yu ZhangKe Zen Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nature Communications 2017, 8, 14041, 10.1038/ncomms14041.Kosaka, N.; Iguchi, H.; Hagiwara, K.; Yoshioka, Y.; Takeshita, F.; Ochiya, T. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J. Biol. Chem. 2013, 288, 10849–10859.
  16. Liang Yang; Xueqiang Peng; Yan Li; Xiaodong Zhang; Yingbo Ma; C L Wu; Qing Fan; Shibo Wei; Hangyu Li; Jingang Liu; et al. Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma. MKerstin Menck; Can Sönmezer; Thomas Stefan Worst; Matthias Schulz; Gry Helene Dihazi; Frank Streit; G. Erdmann; Simon Kling; Michael Boutros; Claudia Binder; Julia Christina Gross; Neutral sphingomyelinases control extracellular vesicles budding from the plasma membrane. Journalecular Cancer of Extracellular Vesicles 2019, 18, 78, 10.1186/s12943-019-0990-6.7, 6, 1378056, 10.1080/20013078.2017.1378056.
  17. Matias Ostrowski; Nuno Carmo; Sophie Krumeich; Isabelle Fanget; Graça Raposo; Ariel Savina; Catarina Ferreira Moita; Kristine Schauer; Alistair Hume; Rui P. Freitas; et al.Bruno GoudPhilippe BenarochNir HacohenMitsunori FukudaClaire DesnosMiguel SeabraFrançois DarchenSebastian AmigorenaLuis MoitaClotilde Théry Rab27a and Rab27b control different steps of the exosome secretion pathway. Yao Wei; Ng Wang; Fangfang Jin; Zhen Bian; Limin Li; Hongwei Liang; Mingzhen Li; Lei Shi; Chaoyun Pan; Dihan Zhu; Xi Chen; Gang Hu; Yuan Liu; Chen Yu Zhang; Ke Zen; Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nature Communications 2009, 12, 19-30, 10.1038/ncb2000.17, 8, 14041, 10.1038/ncomms14041.
  18. Wei‐Chung Cheng; Tsai-Tsen Liao; Chun‐Chi Lin; Lan‐Ting Emily Yuan; Hsin‐Yi Lan; Hung‐Hsin Lin; Hao‐Wei Teng; Hsin‐Chuan Chang; Chi‐Hung Lin; Chih‐Yung Yang; et al.Shih‐Ching HuangJeng‐Kai JiangShung‐Haur YangMuh-Hwa YangWei-Lun Hwang RAB27B‐activated secretion of stem‐like tumor exosomes delivers the biomarker microRNA‐146a‐5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer. InternatiLiang Yang; Xueqiang Peng; Yan Li; Xiaodong Zhang; Yingbo Ma; C L Wu; Qing Fan; Shibo Wei; Hangyu Li; Jingang Liu; Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma. Monal Journal ofecular Cancer 2019, 145, 2209-2224, 10.1002/ijc.32338.8, 78, 10.1186/s12943-019-0990-6.
  19. Graça Raposo; Willem Stoorvogel; Extracellular vesicles: Exosomes, microvesicles, and friends. Journal of Cell Biology 2013, 200, 373-383, 10.1083/jcb.201211138.
  20. Marina Colombo; Graca Raposo; Clotilde Théry; Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles. Annual Review of Cell and Developmental Biology 2014, 30, 255-289, 10.1146/annurev-cellbio-101512-122326.
  21. Theresa L. Whiteside; Exosomes and tumor-mediated immune suppression.. Journal of Clinical Investigation 2016, 126, 1216-23, 10.1172/JCI81136.
  22. Feng Xie; Xiaoxue Zhou; Meiyu Fang; Heyu Li; Peng Su; Yifei Tu; Long Zhang; Fangfang Zhou; Extracellular Vesicles in Cancer Immune Microenvironment and Cancer Immunotherapy.. Advanced Science 2019, 6, 1901779, 10.1002/advs.201901779.
  23. Sayantan Maji; Pankaj Chaudhary; Irina Akopova; Phung M. Nguyen; Richard J. Hare; Ignacy Gryczynski; Jamboor K. Vishwanatha; Exosomal Annexin II Promotes Angiogenesis and Breast Cancer Metastasis.. Molecular Cancer Research 2016, 15, 93-105, 10.1158/1541-7786.MCR-16-0163.
  24. Mitsuru Chiba; Shiori Kubota; Konomi Sato; Satoru Monzen; Exosomes released from pancreatic cancer cells enhance angiogenic activities via dynamin-dependent endocytosis in endothelial cells in vitro.. Scientific Reports 2018, 8, 11972, 10.1038/s41598-018-30446-1.
  25. Hai-Li Lang; Guo-Wen Hu; Bo Zhang; Wei Kuang; Yong Chen; Lei Wu; Guo-Hai Xu; Glioma cells enhance angiogenesis and inhibit endothelial cell apoptosis through the release of exosomes that contain long non-coding RNA CCAT2. Oncology Reports 2017, 38, 785-798, 10.3892/or.2017.5742.
  26. Aikaterini Emmanouilidi; Dino Paladin; David Greening; Marco Falasca; Oncogenic and Non‐Malignant Pancreatic Exosome Cargo Reveal Distinct Expression of Oncogenic and Prognostic Factors Involved in Tumor Invasion and Metastasis. PROTEOMICS 2019, 19, e1800158, 10.1002/pmic.201800158.
  27. Min Li; Ying Lu; Yunchao Xu; Jingwen Wang; Chenghong Zhang; Yue Du; Lu Wang; Lianhong Li; Bo Wang; Jie Shen; Jianwu Tang; Bo Song; Horizontal transfer of exosomal CXCR4 promotes murine hepatocarcinoma cell migration, invasion and lymphangiogenesis. Gene 2018, 676, 101-109, 10.1016/j.gene.2018.07.018.
  28. Chen, Y.; Zeng, C.; Zhan, Y.; Wang, H.; Jiang, X.; Li, W. Aberrant low expression of p85alpha in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b. Oncogene 2017, 36, 4692–4705.
  29. Bruno Costa-Silva; Nicole Aiello; Allyson J. Ocean; Swarnima Singh; Haiying Zhang; Basant Kumar Thakur; Annette Becker; Ayuko Hoshino; Milica Tešić Mark; Henrik Molina; Jenny Xiang; Tuo Zhang; Till-Martin Theilen; Guillermo García-Santos; Caitlin Williams; Yonathan Ararso; Yujie Huang; Gonçalo Rodrigues; Tang-Long Shen; Knut Jørgen Labori; Inger Marie Bowitz Lothe; Elin H. Kure; Jonathan Hernandez; Alexandre Doussot; Saya H. Ebbesen; Paul M. Grandgenett; Michael A. Hollingsworth; Maneesh Jain; Kavita Mallya; Surinder K. Batra; William R. Jarnagin; Robert E. Schwartz; Irina Matei; Hector Peinado; Ben Z. Stanger; Jacqueline Bromberg; David C. Lyden; Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature 2015, 17, 816-826, 10.1038/ncb3169.
  30. Inbal Wortzel; Shani Dror; Candia M. Kenific; David Lyden; Exosome-Mediated Metastasis: Communication from a Distance. Developmental Cell 2019, 49, 347-360, 10.1016/j.devcel.2019.04.011.
  31. Chi Lam Au Yeung; Ngai-Na Co; Tetsushi Tsuruga; Tsz-Lun Yeung; Suet Ying Kwan; Cecilia S. Leung; Yong Li; Edward S. Lu; Kenny Kwan; Kwong Kwok Wong; Rosemarie Schmandt; Karen H. Lu; Samuel C. Mok; Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nature Communications 2016, 7, 11150, 10.1038/ncomms11150.
  32. Mirjam C. Boelens; Tony James Wu; Barzin Y. Nabet; Bihui Xu; Yu Qiu; Taewon Yoon; Diana Azzam; Christina Twyman-Saint Victor; Brianne Z. Wiemann; Hemant Ishwaran; Petra J. Ter Brugge; Jos Jonkers; Joyce Slingerland; Andy J. Minn; Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.. Cell 2014, 159, 499-513, 10.1016/j.cell.2014.09.051.
  33. Kosaka, N.; Iguchi, H.; Hagiwara, K.; Yoshioka, Y.; Takeshita, F.; Ochiya, T. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J. Biol. Chem. 2013, 288, 10849–10859.
  34. Kerstin Menck; Can Sönmezer; Thomas Stefan Worst; Matthias Schulz; Gry Helene Dihazi; Frank Streit; G. Erdmann; Simon Kling; Michael Boutros; Claudia Binder; Julia Christina Gross; Neutral sphingomyelinases control extracellular vesicles budding from the plasma membrane. Journal of Extracellular Vesicles 2017, 6, 1378056, 10.1080/20013078.2017.1378056.
  35. Yao Wei; Ng Wang; Fangfang Jin; Zhen Bian; Limin Li; Hongwei Liang; Mingzhen Li; Lei Shi; Chaoyun Pan; Dihan Zhu; Xi Chen; Gang Hu; Yuan Liu; Chen Yu Zhang; Ke Zen; Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nature Communications 2017, 8, 14041, 10.1038/ncomms14041.
  36. Liang Yang; Xueqiang Peng; Yan Li; Xiaodong Zhang; Yingbo Ma; C L Wu; Qing Fan; Shibo Wei; Hangyu Li; Jingang Liu; Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma. Molecular Cancer 2019, 18, 78, 10.1186/s12943-019-0990-6.
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