Targeting immune regulatory networks to counteract immune suppression in cancer

Vaccines

Volumn 4, Issue 4, 2016, Pages

  Camisaschi, Chiara ^a   Vallacchi, Viviana ^a   Vergani, Elisabetta ^a   Tazzari, Marcella ^a,c   Ferro, Simona ^a   Tuccitto, Alessandra ^a   Kuchuk, Olga ^b   Shahaj, Eriomina ^a   Sulsenti, Roberta ^a   Castelli, Chiara ^a   Rodolfo, Monica ^a   Rivoltini, Licia ^a   Huber, Veronica ^a  

^a NATIONAL CANCER INSTITUTE   (Italy)

^b MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^c RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Cancer; Extracellular vesicles; Immune suppression; Myeloid derived suppressor cells; Regulatory T cells; Therapy; Tumor acidity

Indexed keywords

BARDOXOLONE METHYL; BORTEZOMIB; CALCIFEDIOL; CELECOXIB; CUCURBITACIN; CYCLOPHOSPHAMIDE; DACLIZUMAB; DENILEUKIN DIFTITOX; DOXORUBICIN; FLUOROURACIL; GEMCITABINE; IMATINIB; IPILIMUMAB; NIVOLUMAB; OMAVELOXOLONE; REACTIVE OXYGEN METABOLITE; RETINOIC ACID; SILDENAFIL; SORAFENIB; STAT3 PROTEIN; SUNITINIB; TADALAFIL; VEMURAFENIB;

ACIDIFICATION; ADAPTIVE IMMUNITY; BONE MARROW CELL; CANCER CONTROL; CANCER GROWTH; CANCER IMMUNOTHERAPY; CANCER SURVIVAL; CELL COMMUNICATION; CELL DIFFERENTIATION; CHRONIC INFLAMMATION; EXOSOME; HUMAN; IMMUNE DEFICIENCY; IMMUNE RESPONSE; IMMUNOLOGICAL MONITORING; IMMUNOMODULATION; IMMUNOREGULATION; IMMUNOSTIMULATION; NEOPLASM; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REGULATORY T LYMPHOCYTE; REVIEW; SUPPRESSOR CELL; TREATMENT RESPONSE; TUMOR GROWTH; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT;

EID: 85016863670     PISSN: None     EISSN: 2076393X     Source Type: Journal    
DOI: 10.3390/vaccines4040038     Document Type: Review

References (110)

1. Kyi, C., Postow, M.A. Immune checkpoint inhibitor combinations in solid tumors: Opportunities and challenges. Immunotherapy 2016, 8, 821-837. [CrossRef] [PubMed]
2. Mahoney, K.M., Rennert, P.D., Freeman, G.J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 2015, 14, 561-584. [CrossRef] [PubMed]
3. Gillies, R.J., Gatenby, R.A. Metabolism and its sequelae in cancer evolution and therapy. Cancer J. 2015, 21, 88-96. [CrossRef] [PubMed]
4. Romero-Garcia, S., Moreno-Altamirano, M.M., Prado-Garcia, H., Sánchez-García, F.J. Lactate Contribution to the Tumor Microenvironment: Mechanisms, Effects on Immune Cells and Therapeutic Relevance. Front. Immunol. 2016. [CrossRef] [PubMed]
5. Bussard, K.M., Mutkus, L., Stumpf, K., Gomez-Manzano, C., Marini, F.C. Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res. 2016. [CrossRef] [PubMed]
6. Rutkowski, M.R., Svoronos, N., Perales-Puchalt, A., Conejo-Garcia, J.R. The Tumor Macroenvironment: Cancer-Promoting Networks Beyond Tumor Beds. Adv. Cancer Res. 2015, 128, 235-262. [PubMed]
7. Peinado, H., Alečković, M., Lavotshkin, S., Matei, I., Costa-Silva, B., Moreno-Bueno, G., Hergueta-Redondo, M., Williams, C., García-Santos, G., Ghajar, C., et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 2012, 18, 883-891. [CrossRef] [PubMed]
8. Seubert, B., Grünwald, B., Kobuch, J., Cui, H., Schelter, F., Schaten, S., Siveke, J.T., Lim, N.H., Nagase, H., Simonavicius, N., et al. Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology 2015, 61, 238-248. [CrossRef] [PubMed]
9. Bronte, V., Brandau, S., Chen, S.H., Colombo, M.P., Frey, A.B., Greten, T.F., Mandruzzato, S., Murray, P.J., Ochoa, A., Ostrand-Rosenberg, S., et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 2016, 7, 12150. [CrossRef] [PubMed]
10. Marvel, D., Gabrilovich, D.I. Myeloid-derived suppressor cells in the tumor microenvironment: Expect the unexpected. J. Clin. Investig. 2015, 125, 3356-3364. [CrossRef] [PubMed]
11. Filipazzi, P., Huber, V., Rivoltini, L. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol. Immunother. 2012, 61, 255-263. [CrossRef] [PubMed]
12. Filipazzi, P., Valenti, R., Huber, V., Pilla, L., Canese, P., Iero, M., Castelli, C., Mariani, L., Parmiani, G., Rivoltini, L. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J. Clin. Oncol. 2007, 25, 2546-2553. [CrossRef] [PubMed]
13. Yuan, X.K., Zhao, X.K., Xia, Y.C., Zhu, X., Xiao, P. Increased circulating immunosuppressive CD14(+)HLA-DR(-/low) cells correlate with clinical cancer stage and pathological grade in patients with bladder carcinoma. J. Int. Med. Res. 2011, 39, 1381-1391. [CrossRef] [PubMed]
14. Arihara, F., Mizukoshi, E., Kitahara, M., Takata, Y., Arai, K., Yamashita, T., Nakamoto, Y., Kaneko, S. Increase in CD14+HLA-DR/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol. Immunother. 2013, 62, 1421-1430. [CrossRef] [PubMed]
15. Jordan, K.R., Amaria, R.N., Ramirez, O., Callihan, E.B., Gao, D., Borakove, M., Manthey, E., Borges, V.F., McCarter, M.D. Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol. Immunother. 2013, 62, 1711-1722. [CrossRef] [PubMed]
16. Weide, B., Martens, A., Zelba, H., Stutz, C., Derhovanessian, E., Di Giacomo, A.M., Maio, M., Sucker, A., Schilling, B., Schadendorf, D., et al. Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: Comparison with regulatory T cells and NY-ESO-1-or melan-A-specific T cells. Clin. Cancer Res. 2014, 20, 1601-1609. [CrossRef] [PubMed]
17. Meyer, C., Cagnon, L., Costa-Nunes, CM., Baumgaertner, P., Montandon, N., Leyvraz, L., Michielin, O., Romano, E., Speiser, D.E. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 2014, 63, 247-257. [CrossRef] [PubMed]
18. Huang, A., Zhang, B., Wang, B., Zhang, F., Fan, K.X., Guo, Y.J. Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol. Immunother. 2013, 62, 1439-1451. [CrossRef] [PubMed]
19. Sade-Feldman, M., Kanterman, J., Klieger, Y., Ish-Shalom, E., Mizrahi, O., Saragovi, A., Shtainberg, H., Lotem, M., Baniyash, M. Clinical significance of circulating CD33+CD11b+HLA-DR- myeloid cells in Stage-IV melanoma patients treated with ipilimumab. Clin. Cancer Res. 2016. [CrossRef] [PubMed]
20. Bjoern, J., Juul Nitschke, N., Zeeberg Iversen, T., Schmidt, H., Fode, K., Svane, I.M. Immunological correlates of treatment and response in stage IV malignant melanoma patients treated with Ipilimumab. Oncoimmunology 2015, 5, e1100788. [CrossRef] [PubMed]
21. Gebhardt, C., Sevko, A., Jiang, H., Lichtenberger, R., Reith, M., Tarnanidis, K., Holland-Letz, T., Umansky, L., Beckhove, P., Sucker, A., et al. Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab. Clin. Cancer Res. 2015, 21, 5453-5459. [CrossRef] [PubMed]
22. Nywening, T.M., Wang-Gillam, A., Sanford, D.E., Belt, B.A., Panni, R.Z., Cusworth, B.M., Toriola, A.T., Nieman, R.K., Worley, L.A., Yano, M., et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: A single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016, 17, 651-662. [CrossRef]
23. Mitchem, J.B., Brennan, D.J., Knolhoff, B.L., Belt, B.A., Zhu, Y., Sanford, D.E., Belaygorod, L., Carpenter, D., Collins, L., Piwnica-Worms, D., et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013, 73, 1128-1141. [CrossRef] [PubMed]
24. Condamine, T., Gabrilovich, D.I. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011, 32, 19-25. [CrossRef] [PubMed]
25. Ko, J.S., Zea, A.H., Rini, B.I., Ireland, J.L., Elson, P., Cohen, P., Golshayan, A., Rayman, P.A., Wood, L., Garcia, J., et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 2009, 15, 2148-2157. [CrossRef] [PubMed]
26. Kapanadze, T., Gamrekelashvili, J., Ma, C., Chan, C., Zhao, F., Hewitt, S., Zender, L., Kapoor, V., Felsher, D.W., Manns, M.P., et al. Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. J. Hepatol. 2013, 59, 1007-1013. [CrossRef] [PubMed]
27. Tazzari, M., Negri, T., Rini, F., Vergani, B., Huber, V., Villa, A., Dagrada, P., Colombo, C., Fiore, M., Gronchi, A., et al. Adaptive immune contexture at the tumour site and downmodulation of circulating myeloid-derived suppressor cells in the response of solitary fibrous tumour patients to anti-angiogenic therapy. Br. J. Cancer. 2014, 111, 1350-1362. [CrossRef] [PubMed]
28. Vasquez-Dunddel, D., Pan, F., Zeng, Q., Gorbounov, M., Albesiano, E., Fu, J., Blosser, R.L., Tam, A.J., Bruno, T., Zhang, H., et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J. Clin. Investig. 2013, 123, 1580-1589. [CrossRef] [PubMed]
29. Lu, P., Yu, B., Xu, J. Cucurbitacin B regulates immature myeloid cell differentiation and enhances antitumor immunity in patients with lung cancer. Cancer Biother. Radiopharm. 2012, 1, 495-503. [CrossRef] [PubMed]
30. Hossain, D.M., Pal, S.K., Moreira, D., Duttagupta, P., Zhang, Q., Won, H., Jones, J., D’Apuzzo, M., Forman, S., Kortylewski, M. TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients. Clin. Cancer Res. 2015, 21, 3771-3782. [CrossRef] [PubMed]
31. Kumar, V., Cheng, P., Condamine, T., Mony, S., Languino, L.R., McCaffrey, J.C., Hockstein, N., Guarino, M., Masters, G., Penman, E., et al. CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation. Immunity 2016, 44, 303-315. [CrossRef] [PubMed]
32. Mao, Y., Poschke, I., Wennerberg, E., Pico de Coana, Y., Egyhazi Brage, S., Schultz, I., Hansson, J., Masucci, G., Lundqvist, A., Kiessling, R. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res. 2013, 73, 3877-3887. [CrossRef] [PubMed]
33. Serafini, K., Meckel, M., 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, 203, 2691-2702. [CrossRef] [PubMed]
34. Weed, D.T., Vella, J.L., Reis, I.M., de la Fuente, A.C., Gomez, C., Sargi, Z., Nazarian, R., Califano, J., Borrello, I., Serafini, P. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 2015, 21, 39-48. [CrossRef] [PubMed]
35. Nagaraj, S., Youn, J.I., Weber, H., Iclozan, C., Lu, L., Cotter, M.J., Meyer, C., Becerra, C.R., Fishman, M., Antonia, S., et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin. Cancer Res. 2010, 16, 1812-1823. [CrossRef] [PubMed]
36. Wang, Z., Zhang, L., Wang, H., Xiong, S., Li, Y., Tao, Q., Xiao, W., Qin, H., Wang, Y., Zhai, Z. Tumor-induced CD14+HLA-DR (-/low) myeloid-derived suppressor cells correlate with tumor progression and outcome of therapy in multiple myeloma patients. Cancer Immunol. Immunother. 2015, 64, 389-399. [CrossRef] [PubMed]
37. Schilling, B., Sucker, A., Griewank, K., Zhao, F., Weide, B., Gorgens, A., Giebel, B., Schadendorf, D., Paschen, A. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int. J. Cancer 2013, 133, 1653-1663. [CrossRef] [PubMed]
38. Suzuki, E., Kapoor, V., Jassar, A.S., Kaiser, L.R., Albelda, S.M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 2005, 11, 6713-6721. [CrossRef] [PubMed]
39. Vincent, J., Mignot, G., Chalmin, F., Ladoire, S., Bruchard, M., Chevriaux, A., Martin, F., Apetoh, L., Rébé, C., Ghiringhelli, F. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010, 70, 3052-3061. [CrossRef] [PubMed]
40. Alizadeh, D., Trad, M., Hanke, N.T., Larmonier, C.B., Janikashvili, N., Bonnotte, B., Katsanis, E., Larmonier, N. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T cell transfer in breast cancer. Cancer Res. 2014, 74, 104-118. [CrossRef] [PubMed]
41. Lathers, D.M.R., Clark, J.I., Achille, N.J., Young, M.R.I. Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol Immunother. 2004, 53, 422-430. [CrossRef] [PubMed]
42. Wiers, K.M., Lathers, D.M., Wright, M.A., Young, M.R. Vitamin D3 treatment to diminish the levels of immune suppressive CD34+ cells increases the effectiveness of adoptive immunotherapy. J. Immunother. 2000, 23, 115-124. [CrossRef] [PubMed]
43. Mirza, N., Fishman, M., Fricke, I., Dunn, M., Neuger, A.M., Frost, T.J., Lush, R.M., Antonia, S., Gabrilovich, D.I. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006, 66, 9299-9307. [CrossRef] [PubMed]
44. Kumar, V., Gabrilovich, D.I. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology 2014, 143, 512-519. [CrossRef] [PubMed]
45. Olson, B.M., McNeel, D.G. Monitoring Regulatory Immune Responses in Tumor Immunotherapy Clinical Trials. Front. Oncol. 2013. [CrossRef] [PubMed]
46. Liu, C., Workman, C.J. Targeting Regulatory T Cells in Tumors. FEBS J. 2016. [CrossRef] [PubMed]
47. Jacobs, J.F., Punt, C.J., Lesterhuis, W.J., Sutmuller, R.P., Brouwer, H.M., Scharenborg, N.M., Klasen, I.S., Hilbrands, L.B., Figdor, C.G., de Vries, I.J., et al. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: A phase I/II study in metastatic melanoma patients. Clin. Cancer Res. 2010, 16, 5067-5078. [CrossRef] [PubMed]
48. Attia, P., Maker, A.V., Haworth, L.R., Rogers-Freezer, L., Rosenberg, S.A. Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J. Immunother. 2005, 28, 582-592. [CrossRef] [PubMed]
49. Colombo, M.P., Piconese, S. Regulatory-T cell inhibition versus depletion: The right choice in cancer immunotherapy. Nat. Rev. Cancer 2007, 7, 880-887. [CrossRef] [PubMed]
50. Ghiringhelli, F., Menard, C., Puig, P.E., Ladoire, S., Roux, S., Martin, F., Solary, E., le Cesne, A., Zitvogel, L., Chauffert, B. Metronomic cyclophosphamide regimen selectively depletes CD4+ CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 2007, 56, 641-648. [CrossRef] [PubMed]
51. Ge, Y., Domschke, C., Stoiber, N., Schott, S., Heil, J., Rom, J., Blumenstein, M., Thum, J., Sohn, C., Schneeweiss, A., et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: Immunological effects and clinical outcome. Cancer Immunol. Immunother. 2012, 61, 353-362. [CrossRef] [PubMed]
52. Camisaschi, C., Filipazzi, P., Tazzari, M., Casati, C., Beretta, V., Pilla, L., Patuzzo, R., Maurichi, A., Cova, A., Maio, M., et al. Effects of cyclophosphamide and IL-2 on regulatory CD4+ T cell frequency and function in melanoma patients vaccinated with HLA-class I peptides: Impact on the antigen-specific T cell response. Cancer Immunol. Immunother. 2013, 62, 897-908. [CrossRef] [PubMed]
53. Adotevi, O., Pere, H., Ravel, P., Haicheur, N., Badoual, C., Merillon, N., Medioni, J., Peyrard, S., Roncelin, S., Verkarre, V., et al. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J. Immunother. 2010, 33, 991-998. [CrossRef] [PubMed]
54. Desar, I.M., Jacobs, J.H., Hulsbergen-vandeKaa, C.A., Oyen, W.J., Mulders, P.F., van der Graaf, W.T., Adema, G.J., van Herpen, C.M., de Vries, I.J. Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients. Int. J. Cancer. 2010, 129, 507-512. [CrossRef] [PubMed]
55. Larmonier, N., Janikashvili, N., LaCasse, C.J., Larmonier, C.B., Cantrell, J., Situ, E., Lundeen, T., Bonnotte, B., Katsanis, E. Imatinib mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL-tumors. J. Immunol. 2008, 181, 6955-6963. [CrossRef] [PubMed]
56. Topalian, S.L., Drake, C.G., Pardoll, D.M. Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell 2015, 27, 450-461. [CrossRef] [PubMed]
57. Sawant, D.V., Vignali, D.A. Once a Treg, always a Treg? Immunol. Rev. 2014, 259, 173-191. [CrossRef] [PubMed]
58. Liakou, C.I., Kamat, A., Tang, D.N., Chen, H., Sun, J., Troncoso, P., Logothetis, C., Sharma, P. CTLA-4 blockade increases IFNgamma-producing CD4+ ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl. Acad. Sci. USA 2008, 105, 14987-14992. [CrossRef] [PubMed]
59. Ménard, C., Ghiringhelli, F., Roux, S., Chaput, N., Mateus, C., Grohmann, U., Caillat-Zucman, S., Zitvogel, L., Robert, C. Ctla-4 blockade confers lymphocyte resistance to regulatory T cells in advanced melanoma: Surrogate marker of efficacy of tremelimumab? Clin. Cancer Res. 2008, 14, 5242-5249. [CrossRef] [PubMed]
60. Romano, E., Kusio-Kobialka, M., Foukas, P.G., Baumgaertner, P., Meyer, C., Ballabeni, P., Michielin, O., Weide, B., Romero, P., Speiser, D.E. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl. Acad. Sci. USA 2015, 112, 6140-6145. [CrossRef] [PubMed]
61. Wang, W., Lau, R., Yu, D., Zhu, W., Korman, A., Weber, J. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int. Immunol. 2009, 21, 1065-1077. [CrossRef] [PubMed]
62. Valzasina, B., Guiducci, C., Dislich, H., Killeen, N., Weinberg, A.D., Colombo, M.P. Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: A novel regulatory role for OX40 and its comparison with GITR. Blood 2005, 105, 2845-2851. [CrossRef] [PubMed]
63. Camisaschi, C., Casati, C., Rini, F., Perego, M., De Filippo, A., Triebel, F., Parmiani, G., Belli, F., Rivoltini, L., Castelli, C. LAG-3 expression defines a subset of CD4+CD25(high)Foxp3+ regulatory T cells that are expanded at tumor sites. J. Immunol. 2010, 184, 6545-6551. [CrossRef] [PubMed]
64. Matsuzaki, J., Gnjatic, S., Mhawech-Fauceglia, P., Beck, A., Miller, A., Tsuji, T., Eppolito, C., Qian, F., Lele, S., Shrikant, P., et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG3 and PD1 in human ovarian cancer. Proc. Natl. Acad. Sci. USA 2010, 107, 7875-7880. [CrossRef] [PubMed]
65. Goding, S.R., Wilson, K.A., Xie, Y., Harris, K.M., Baxi, A., Akpinarli, A., Fulton, A., Tamada, K., Strome, S.E., Antony, P.A. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J. Immunol. 2013, 190, 4899-4909. [CrossRef] [PubMed]
66. Lo Cicero, A., Stahl, P.D., Raposo, G. Extracellular vesicles shuffling intercellular messages: For good or for bad. Curr. Opin. Cell Biol. 2015, 35, 69-77. [CrossRef] [PubMed]
67. Tkach, M., Théry, C. Communication by Extracellular Vesicles: WhereWe Are and WhereWe Need to Go. Cell 2016, 164, 1226-1232.
68. Kalluri, R. The biology and function of exosomes in cancer. J. Clin. Investig. 2016, 126, 1208-1215. [CrossRef] [PubMed]
69. Andreola, G., Rivoltini, L., Castelli, C., Huber, V., Perego, P., Deho, P., Squarcina, P., Accornero, P., Lozupone, F., Lugini, L., et al. Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J. Exp. Med. 2002, 195, 1303-1316. [CrossRef] [PubMed]
70. Huber, V., Fais, S., Iero, M., Lugini, L., Canese, P., Squarcina, P., Zaccheddu, A., Colone, M., Arancia, G., Gentile, M., et al. Human colorectal cancer cells induce T cell death through release of proapoptotic microvesicles: Role in immune escape. Gastroenterology 2005, 128, 1796-1804. [CrossRef] [PubMed]
71. Valenti, R., Huber, V., Filipazzi, P., Pilla, L., Sovena, G., Villa, A., Corbelli, A., Fais, S., Parmiani, G., Rivoltini, L. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res. 2006, 66, 9290-9298. [CrossRef] [PubMed]
72. Whiteside, T.L. Exosomes and tumor-mediated immune suppression. J. Clin. Investig. 2016, 126, 1216-1223. [CrossRef] [PubMed]
73. Yuana, Y., Böing, A.N., Grootemaat, A.E., van der Pol, E., Hau, C.M., Cizmar, P., Buhr, E., Sturk, A., Nieuwland, R. Handling and storage of human body fluids for analysis of extracellular vesicles. J. Extracell. Vesicles 2015. [CrossRef] [PubMed]
74. Boukouris, S., Mathivanan, S. Exosomes in bodily fluids are a highly stable resource of disease biomarkers. Proteom. Clin. Appl. 2015, 9, 358-367. [CrossRef] [PubMed]
75. Zocco, D., Ferruzzi, P., Cappello, F., Kuo, W.P., Fais, S. Extracellular vesicles as shuttles of tumor biomarkers and anti-tumor drugs. Front. Oncol. 2014. [CrossRef] [PubMed]
76. Melo, S.A., Luecke, L.B., Kahlert, C., Fernandez, A.F., Gammon, S.T., Kaye, J., LeBleu, V.S., Mittendorf, E.A., Weitz, J., Rahbari, N., et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015, 523, 177-182. [CrossRef] [PubMed]
77. Zitvogel, L., Regnault, A., Lozier, A., Wolfers, J., Flament, C., Tenza, D., Ricciardi-Castagnoli, P., Raposo, G., Amigorena, S. Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes. Nat. Med. 1998, 4, 594-600. [CrossRef] [PubMed]
78. Pitt, J.M., André, F., Amigorena, S., Soria, J.C., Eggermont, A., Kroemer, G., Zitvogel, L. Dendritic cell-derived exosomes for cancer therapy. J. Clin. Investig. 2016, 126, 1224-1232. [CrossRef] [PubMed]
79. Zhang, X., Pei, Z., Chen, J., Ji, C., Xu, J., Zhang, X., Wang, J. Exosomes for Immunoregulation and Therapeutic Intervention in Cancer. J. Cancer 2016, 7, 1081-1087. [CrossRef] [PubMed]
80. Kunigelis, K.E., Graner, M.W. The Dichotomy of Tumor Exosomes (TEX) in Cancer Immunity: Is It All in the ConTEXt? Vaccines 2015, 3, 1019-1051. [CrossRef] [PubMed]
81. Fais, S., O’Driscoll, L., Borras, F.E., Buzas, E., Camussi, G., Cappello, F., Carvalho, J., Cordeiro da Silva, A., Del Portillo, H., El Andaloussi, S., et al. Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine. ACS Nano 2016, 10, 3886-3899. [CrossRef] [PubMed]
82. Rivoltini, L., Chiodoni, C., Squarcina, P., Tortoreto, M., Villa, A., Vergani, B., Bürdek, M., Botti, L., Arioli, I., Cova, A., et al. TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Armed Exosomes Deliver Proapoptotic Signals to Tumor Site. Clin. Cancer Res. 2016, 22, 3499-3512. [CrossRef] [PubMed]
83. Condamine, T., Kumar, V., Ramachandran, I.R., Youn, J.I., Celis, E., Finnberg, N., El-Deiry, W.S., Winograd, R., Vonderheide, R.H., English, N.R., et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Investig. 2014, 124, 2626-2639. [CrossRef] [PubMed]
84. Lugini, L., Cecchetti, S., Huber, V., Luciani, F., Macchia, G., Spadaro, F., Paris, L., Abalsamo, L., Colone, M., Molinari, A., et al. Immune surveillance properties of human NK cell-derived exosomes. J. Immunol. 2012, 189, 2833-2842. [CrossRef] [PubMed]
85. Munagala, R., Aqil, F., Jeyabalan, J., Gupta, R.C. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2016, 371, 48-61. [CrossRef] [PubMed]
86. Wang, Q., Ren, Y., Mu, J., Egilmez, N.K., Zhuang, X., Deng, Z., Zhang, L., Yan, J., Miller, D., Zhang, H.G. Grapefruit-Derived Nanovectors Use an Activated Leukocyte Trafficking Pathway to Deliver Therapeutic Agents to Inflammatory Tumor Sites. Cancer Res. 2015, 75, 2520-2529. [CrossRef] [PubMed]
87. Raimondo, S., Naselli, F., Fontana, S., Monteleone, F., Lo Dico, A., Saieva, L., Zito, G., Flugy, A., Manno, M., Di Bella, M.A., et al. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death. Oncotarget 2015, 6, 19514-19527. [CrossRef] [PubMed]
88. Sun, D., Zhuang, X., Xiang, X., Liu, Y., Zhang, S., Liu, C., Barnes, S., Grizzle, W., Miller, D., Zhang, H.G. A novel nanoparticle drug delivery system: The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 2010, 18, 1606-1614. [CrossRef] [PubMed]
89. Gobbo, J., Marcion, G., Cordonnier, M., Dias, A.M., Pernet, N., Hammann, A., Richaud, S., Mjahed, H., Isambert, N., Clausse, V., et al. Restoring Anticancer Immune Response by Targeting Tumor-Derived ExosomesWith a HSP70 Peptide Aptamer. J. Natl. Cancer Inst. 2015. [CrossRef] [PubMed]
90. Bryniarski, K., Ptak, W., Jayakumar, A., Püllmann, K., Caplan, M.J., Chairoungdua, A., Lu, J., Adams, B.D., Sikora, E., Nazimek, K., et al. Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T cell microRNA-150 to effector T cells to inhibit contact sensitivity. J. Allergy Clin. Immunol. 2013, 132, 170-181. [CrossRef] [PubMed]
91. Marleau, A.M., Chen, C.S., Joyce, J.A., Tullis, R.H. Exosome removal as a therapeutic adjuvant in cancer. J. Transl. Med. 2012. [CrossRef] [PubMed]
92. Ciravolo, V., Huber, V., Ghedini, G.C., Venturelli, E., Bianchi, F., Campiglio, M., Morelli, D., Villa, A., Della Mina, P., Menard, S., et al. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J. Cell Physiol. 2012, 227, 658-667. [CrossRef] [PubMed]
93. Aung, T., Chapuy, B., Vogel, D., Wenzel, D., Oppermann, M., Lahmann, M., Weinhage, T., Menck, K., Hupfeld, T., Koch, R., et al. Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3. Proc. Natl. Acad. Sci. USA 2011, 108, 15336-15341. [CrossRef] [PubMed]
94. Nagaraj, S., Gabrilovich, D.I. Myeloid-derived suppressor cells in human cancer. Cancer J. 2010, 16, 348-353. [CrossRef] [PubMed]
95. Hanahan, D., Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646-674. [CrossRef] [PubMed]
96. Fang, J.S., Gillies, R.D., Gatenby, R.A. Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin. Cancer Biol. 2008, 18, 330-337. [CrossRef] [PubMed]
97. Calcinotto, A., Filipazzi, P., Grioni, M., Iero, M., De Milito, A., Ricupito, A., Cova, A., Canese, R., Jachetti, E., Rossetti, M., et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012, 72, 2746-2756. [CrossRef] [PubMed]
98. Bellone, M., Calcinotto, A., Filipazzi, P., De Milito, A., Fais, S., Rivoltini, L. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology 2013, 2, e22058. [CrossRef] [PubMed]
99. Corzo, C.A., Condamine, T., Lu, L., Cotter, M.J., Youn, J.I., Cheng, P., Cho, H.I., Celis, E., Quiceno, D.G., Padhya, T., et al. HIF-1α regulates function and differentiation of myeloidderived suppressor cells in the tumor microenvironment. J. Exp. Med. 2010, 207, 2439-2453. [CrossRef] [PubMed]
100. Noman, M.Z., Desantis, G., Janji, B., Hasmim, M., Karray, S., Dessen, P., Bronte, V., Chouaib, S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 2014, 211, 781-790. [CrossRef] [PubMed]
101. Choi, S.Y., Collins, C.C., Gout, P.W., Wang, Y. Cancer-generated lactic acid: A regulatory, immunosuppressive metabolite? J. Pathol. 2013, 230, 350-355. [CrossRef] [PubMed]
102. Fais, S., Venturi, G., Gatenby, B. Microenvironmental acidosis in carcinogenesis and metastases: New strategies in prevention and therapy. Cancer Metastasis Rev. 2014, 33, 1095-1108. [CrossRef] [PubMed]
103. Wang, B.Y., Zhang, J., Wang, J.L., Sun, S., Wang, Z.H., Wang, L.P., Zhang, Q.L., Lv, F.F., Cao, E.Y., Shao, Z.M., et al. Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. J. Exp. Clin. Cancer Res. 2015. [CrossRef]
104. Ferrari, S., Perut, F., Fagioli, F., Brach Del Prever, A., Meazza, C., Parafioriti, A., Picci, P., Gambarotti, M., Avnet, S., Baldini, N., et al. Proton pump inhibitor chemosensitization in human osteosarcoma: From the bench to the patients’ bed. J. Transl. Med. 2013. [CrossRef] [PubMed]
105. Supuran, C.T. Structure and function of carbonic anhydrases. Biochem. J. 2016, 473, 2023-2032. [CrossRef] [PubMed]
106. Chafe, S.C., Lou, Y., Sceneay, J., Vallejo, M., Hamilton, M.J., McDonald, P.C., Bennewith, K.L., Möller, A., Dedhar, S. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production. Cancer Res. 2015, 75, 996-1008. [CrossRef] [PubMed]
107. Khazaie, K., Blatner, N.R., Khan, M.W., Gounari, F., Gounaris, E., Dennis, K., Bonertz, A., Tsai, F.N., Strouch, M.J., Cheon, E., et al. The significant role of mast cells in cancer. Cancer Metastasis Rev. 2011, 30, 45-60. [CrossRef] [PubMed]
108. Lamers, C.H., Sleijfer, S., Vulto, A.G., Kruit, W.H., Kliffen, M., Debets, R., Gratama, J.W., Stoter, G., Oosterwijk, E. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: First clinical experience. J. Clin. Oncol. 2006, 24, e20-e22. [CrossRef] [PubMed]
109. Ibrahim-Hashim, A., Cornnell, H.H., Abrahams, D., Lloyd, M., Bui, M., Gillies, R.J., Gatenby, R.A. Systemic buffers inhibit carcinogenesis in TRAMP mice. J. Urol. 2012, 188, 624-631. [CrossRef] [PubMed]
110. Pilon-Thomas, S., Kodumudi, K.N., El-Kenawi, A.E., Russell, S., Weber, A.M., Luddy, K., Damaghi, M., Wojtkowiak, J.W., Mulé, J.J., et al. Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy. Cancer Res. 2016, 76, 1381-1390. [CrossRef] [PubMed]