Blockade of surface-bound TGF-ß on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment

Science Signaling

Volumn 10, Issue 494, 2017, Pages

  Budhu, Sadna ^a   Schaer, David A ^a   Li, Yongbiao ^a   Toledo Crow, Ricardo ^a   Panageas, Katherine ^a   Yang, Xia ^a   Zhong, Hong ^a   Houghton, Alan N ^a   Silverstein, Samuel C ^b   Merghoub, Taha ^a   Wolchok, Jedd D ^a,c  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b Department of Medicine   (United States)

^c WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GRANZYME B; NEUTRALIZING ANTIBODY; PROGRAMMED DEATH 1 RECEPTOR; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA ANTIBODY; GRANZYME; PDCD1 PROTEIN, HUMAN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; B16-F10 CELL LINE; B16-OVA CELL LINE; CANCER IMMUNOTHERAPY; CD8+ T LYMPHOCYTE; CELL CONTACT; CONTROLLED STUDY; EFFECTOR CELL; EX VIVO STUDY; FEMALE; IMMUNOSUPPRESSIVE TREATMENT; IN VIVO STUDY; MELANOMA B16; MOUSE; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; T CELL DEPLETION; T LYMPHOCYTE ACTIVATION; TUMOR GROWTH; TUMOR MICROENVIRONMENT; ANIMAL; C57BL MOUSE; CELL COMMUNICATION; CELLULAR IMMUNITY; COCULTURE; IMMUNOLOGY; METABOLISM; SECRETION (PROCESS); TRANSGENIC MOUSE; TUMOR CELL LINE;

ANIMALS; ANTIBODIES, NEUTRALIZING; CD8-POSITIVE T-LYMPHOCYTES; CELL COMMUNICATION; CELL LINE, TUMOR; COCULTURE TECHNIQUES; FEMALE; GRANZYMES; IMMUNITY, CELLULAR; IMMUNOSUPPRESSION; MICE; MICE, INBRED C57BL; MICE, TRANSGENIC; PROGRAMMED CELL DEATH 1 RECEPTOR; T-LYMPHOCYTES, REGULATORY; TRANSFORMING GROWTH FACTOR BETA; TUMOR MICROENVIRONMENT;

EID: 85028698841     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.aak9702     Document Type: Article

References (37)

1. D. Mittal, M. M. Gubin, R. D. Schreiber, M. J. Smyth, New insights into cancer immunoediting and its three component phases—Elimination, equilibrium and escape. Curr. Opin. Immunol. 27, 16–25 (2014).
2. R. D. Schreiber, L. J. Old, M. J. Smyth, Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
3. A. D. Cohen, D. A. Schaer, C. Liu, Y. Li, D. Hirschhorn-Cymmerman, S. C. Kim, A. Diab, G. Rizzuto, F. Duan, M. A. Perales, T. Merghoub, A. N. Houghton, J. D. Wolchok, Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLOS ONE 5, e10436 (2010).
4. K. Klages, C. T. Mayer, K. Lahl, C. Loddenkemper, M. W. L. Teng, S. F. Ngiow, M. J. Smyth, A. Hamann, J. Huehn, T. Sparwasser, Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res. 70, 7788–7799 (2010).
5. X. Li, E. Kostareli, J. Suffner, N. Garbi, G. J. Hämmerling, Efficient Treg depletion induces T-cell infiltration and rejection of large tumors. Eur. J. Immunol. 40, 3325–3335 (2010).
6. D. Hirschhorn-Cymerman, G. A. Rizzuto, T. Merghoub, A. D. Cohen, F. Avogadri, A. M. Lesokhin, A. D. Weinberg, J. D. Wolchok, A. N. Houghton, OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J. Exp. Med. 206, 1103–1116 (2009).
7. S. A. Quezada, K. S. Peggs, M. A. Curran, J. P. Allison, CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Invest. 116, 1935–1945 (2006).
8. A. Schmidt, N. Oberle, P. H. Krammer, Molecular mechanisms of Treg-mediated T cell suppression. Front. Immunol. 3, 51 (2012).
9. A. Schmidt, N. Oberle, E.-M. Weiß, D. Vobis, S. Frischbutter, R. Baumgrass, C. S. Falk, M. Haag, B. Brügger, H. Lin, G. W. Mayr, P. Reichardt, M. Gunzer, E. Suri-Payer, P. H. Krammer, Human regulatory T cells rapidly suppress T cell receptor–induced Ca2+, NF-kB, and NFAT signaling in conventional T cells. Sci. Signal. 4, ra90 (2011).
10. D. A. Schaer, Y. Li, T. Merghoub, G. A. Rizzuto, A. Shemesh, A. D. Cohen, Y. Li, F. Avogadri, R. Toledo-Crow, A. N. Houghton, J. D. Wolchok, Detection of intra-tumor self antigen recognition during melanoma tumor progression in mice using advanced multimode confocal/two photon microscope. PLOS ONE 6, e21214 (2011).
11. S. Budhu, J. D. Loike, A. Pandolfi, S. Han, G. Catalano, A. Constantinescu, R. Clynes, S. C. Silverstein, CD8+ T cell concentration determines their efficiency in killing cognate antigen–expressing syngeneic mammalian cells in vitro and in mouse tissues. J. Exp. Med. 207, 223–235 (2010).
12. A. M. Lesokhin, T. M. Hohl, S. Kitano, C. Cortez, D. Hirschhorn-Cymerman, F. Avogadri, G. A. Rizzuto, J. J. Lazarus, E. G. Pamer, A. N. Houghton, T. Merghoub, J. D. Wolchok, Monocytic CCR2+ myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res. 72, 876–886 (2012).
13. D. A. Schaer, S. Budhu, C. Liu, C. Bryson, N. Malandro, A. Cohen, H. Zhong, X. Yang, A. N. Houghton, T. Merghoub, J. D. Wolchok, GITR pathway activation abrogates tumor immune suppression through loss of regulatory T-cell lineage stability. Cancer Immunol. Res. 1, 320–331 (2013).
14. M.-L. Chen, M. J. Pittet, L. Gorelik, R. A. Flavell, R. Weissleder, H. von Boehmer, K. Khazaie, Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proc. Natl. Acad. Sci. U.S.A. 102, 419–424 (2005).
15. L. W. Collison, V. Chaturvedi, A. L. Henderson, P. R. Giacomin, C. Guy, J. Bankoti, D. Finkelstein, K. Forbes, C. J. Workman, S. A. Brown, J. E. Rehg, M. L. Jones, H.-T. Ni, D. Artis, M. J. Turk, D. A. A. Vignali, IL-35-mediated induction of a potent regulatory T cell population. Nat. Immunol. 11, 1093–1101 (2010).
16. X. Cao, S. F. Cai, T. A. Fehniger, J. Song, L. I. Collins, D. R. Piwnica-Worms, T. J. Ley, Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27, 635–646 (2007).
17. L. Gorelik, R. A. Flavell, Immune-mediated eradication of tumors through the blockade of transforming growth factor-b signaling in T cells. Nat. Med. 7, 1118–1122 (2001).
18. T. R. Mempel, M. J. Pittet, K. Khazaie, W. Weninger, R. Weissleder, H. von Boehmer, U. H. von Andrian, Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006).
19. K. Nakamura, A. Kitani, W. Strober, Cell contact–dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface–bound transforming growth factor b. J. Exp. Med. 194, 629–644 (2001).
20. J. D. Fontenot, J. P. Rasmussen, M. A. Gavin, A. Y. Rudensky, A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).
21. A. L. Smith, T. P. Robin, H. L. Ford, Molecular pathways: Targeting the TGF-β pathway for cancer therapy. Clin. Cancer Res. 18, 4514–4521 (2012).
22. M. Smith, C. Seguin-Devaux, T. B. Oriss, B. Dixon-McCarthy, L. Yang, B. T. Ameredes, T. E. Corcoran, A. Ray, Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3. J. Clin. Invest. 114, 28–38 (2004).
23. J. P. Edwards, A. M. Thornton, E. M. Shevach, Release of active TGF-β1 from the latent TGF-β1/GARP complex on T regulatory cells is mediated by integrin b8. J. Immunol. 193, 2843–2849 (2014).
24. J. Dewever, F. Frerart, C. Bouzin, C. Baudelet, R. Ansiaux, P. Sonveaux, B. Gallez, C. Dessy, O. Feron, Caveolin-1 is critical for the maturation of tumor blood vessels through the regulation of both endothelial tube formation and mural cell recruitment. Am. J. Pathol. 171, 1619–1628 (2007).
25. H. F. Dvorak, J. A. Nagy, B. Berse, L. F. Brown, K.-T. Yeo, T.-K. Yeo, A. M. Dvorak, L. van de Water, T. M. Sioussat, D. R. Senger, Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann. N. Y. Acad. Sci. 667, 101–111 (1992).
26. C. A. Bauer, E. Y. Kim, F. Marangoni, E. Carrizosa, N. M. Claudio, T. R. Mempel, Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J. Clin. Invest. 124, 2425–2440 (2014).
27. M. K. Donkor, A. Sarkar, P. A. Savage, R. A. Franklin, L. K. Johnson, A. A. Jungbluth, J. P. Allison, M. O. Li, T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine. Immunity 35, 123–134 (2011).
28. D. Q. Tran, J. Andersson, R. Wang, H. Ramsey, D. Unutmaz, E. M. Shevach, GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells. Proc. Natl. Acad. Sci. U.S.A. 106, 13445–13450 (2009).
29. M. A. Travis, D. Sheppard, TGF-β activation and function in immunity. Annu. Rev. Immunol. 32, 51–82 (2014).
30. C. Neuzillet, A. Tijeras-Raballand, R. Cohen, J. Cros, S. Faivre, E. Raymond, A. de Gramont, Targeting the TGFb pathway for cancer therapy. Pharmacol. Ther. 147, 22–31 (2015).
31. T. R. Simpson, F. Li, W. Montalvo-Ortiz, M. A. Sepulveda, K. Bergerhoff, F. Arce, C. Roddie, J. Y. Henry, H. Yagita, J. D. Wolchok, K. S. Peggs, J. V. Ravetch, J. P. Allison, S. A. Quezada, Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).
32. Y. Bulliard, R. Jolicoeur, M. Windman, S. M. Rue, S. Ettenberg, D. A. Knee, N. S. Wilson, G. Dranoff, J. L. Brogdon, Activating Fc g receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–1693 (2013).
33. F. Avogadri, R. Zappasodi, A. Yang, S. Budhu, N. Malandro, D. Hirschhorn-Cymerman, S. Tiwari, M. F. Maughan, R. Olmsted, J. D. Wolchok, T. Merghoub, Combination of alphavirus replicon particle–based vaccination with immunomodulatory antibodies: Therapeutic activity in the B16 melanoma mouse model and immune correlates. Cancer Immunol. Res. 2, 448–458 (2014).
34. D. Hirschhorn-Cymerman, S. Budhu, S. Kitano, C. Liu, F. Zhao, H. Zhong, A. M. Lesokhin, F. Avogadri-Connors, J. Yuan, Y. Li, A. N. Houghton, T. Merghoub, J. D. Wolchok, Induction of tumoricidal function in CD4+ T cells is associated with concomitant memory and terminally differentiated phenotype. J. Exp. Med. 209, 2113–2126 (2012).
35. K. A. Hogquist, S. C. Jameson, W. R. Heath, J. L. Howard, M. J. Bevan, F. R. Carbone, T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).
36. W. W. Overwijk, M. R. Theoret, S. E. Finkelstein, D. R. Surman, L. A. de Jong, F. A. Vyth-Dreese, T. A. Dellemijn, P. A. Antony, P. J. Spiess, D. C. Palmer, D. M. Heimann, C. A. Klebanoff, Z. Yu, L. N. Hwang, L. Feigenbaum, A. M. Kruisbeek, S. A. Rosenberg, N. P. Restifo, Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).
37. L. D. Falo Jr., M. Kovacsovics-Bankowski, K. Thompson, K. L. Rock, Targeting antigen into the phagocytic pathway in vivo induces protective tumour immunity. Nat. Med. 1, 649–653 (1995).