T Cell Co-regulatory Signals and Their Role in Cancer Therapy

Chapter
First Online:
Part of the Current Cancer Research book series (CUCR)

Abstract

T cell activation is initiated by signaling through the TCR after binding to MHC-presented antigen. Both positive and negative co-regulatory signaling can modify this original activating signal. T cell co-regulation is provided by receptors on the T cell surface membrane. Inhibitory signals are provided by CTLA4 or PD-1, while co-stimulation is provided by CD28, 4-1BB, OX40, or GITR. These signals are being studied in the laboratory and at the clinical level in order to therapeutically modulate T cell responses to tumor cells. T cells can recognize tumor antigens in the same way that these immune cells recognize bacteria, viral antigens, and other foreign peptides. If appropriately activated by the tumor antigen, the immune system can mediate an antitumor gene response. Unfortunately, immune cells with antitumor specificity are not present in abundance and are often inhibited by tumor expression of CTLA4 or PD-1 ligands. Thus manipulation of co-regulatory signals can be used as a strategy by which to strengthen the immune response, via augmentation of T cell co-stimulation and/or blockade of inhibitory signals, in order to effectively treat cancer. In this chapter we review the basic principles and science as well as the ongoing clinical efforts in this area that have had recent success and offer additional promise.

Keywords

Renal Cell Carcinoma Melanoma Patient Immune Checkpoint Renal Cell Carcinoma Patient Cell Surface Membrane 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Janeway Jr CA, Travers P, Walport M, Shlomchik MJ. Immunobiology; the immune system in health and disease. 6th ed. New York, NY: Garland Science; 2005. p. 26–31. 327-328.Google Scholar
  2. 2.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:254–62.CrossRefGoogle Scholar
  3. 3.
    Sansom DM. CD28, CTLA4, and their ligands: who does what and to whom? Immunology. 2000;101:169–77.PubMedCrossRefGoogle Scholar
  4. 4.
    Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;19:355–66.CrossRefGoogle Scholar
  6. 6.
    Capece D, Verzella D, Fischietti M, Zazzeroni F, Alesse E. Targeting costimulatory molecules to improve antitumor immunity. J Biomed Biotechnol. 2012;2011:1–17.CrossRefGoogle Scholar
  7. 7.
    Poirier N, Blancho G, Vanhove B. CD28-Specific immunomodulating antibodies: what can be learned from experimental models. Am J Transplant. 2012;7:1682–90.CrossRefGoogle Scholar
  8. 8.
    Topalian SL, Drake CG, Pardoll DM. Targetting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immmunol. 2012;24:207–12.CrossRefGoogle Scholar
  9. 9.
    Sharpe AH, Wherry JE, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–45.PubMedCrossRefGoogle Scholar
  10. 10.
    Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Titanji K, Velu V, Chennareddi L, Vijay-Kumar M, Gewirtz AT, Freeman GJ, Amara RR. Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques. J Clin Invest. 2010;120:3878–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015–29.PubMedCrossRefGoogle Scholar
  13. 13.
    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhang H, Snyder KM, Suhoski MM, Maus MV, Kapoor V, June CH, Mackall CL. 4-1BB Is superior to CD28 costimulation for generating CD8+ cytotoxic lymphocytes for adoptive immunotherapy. J Immunol. 2007;179:4910–8.PubMedGoogle Scholar
  16. 16.
    Vinay DS, Kwon BS. Immunotherapy of cancer with 4-1BB. Mol Cancer Ther. 2012;11:1062–70.PubMedCrossRefGoogle Scholar
  17. 17.
    Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity. Nat Rev Immunol. 2003;3:609–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Mittler RS, Bailey TS, Klussman K, Trailsmith MD, Hoffmann MK. Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy. J Exp Med. 1999;190:1535–40.PubMedCrossRefGoogle Scholar
  19. 19.
    Hong HJ, Lee JW, Park SS, Kang YJ, Chang SY, Kim KM, Kim JO, Murthy KK, Payne JS, Yoon SK, Park MJ, Kim IC, Kim JG, Kang CY. A humanized anti-4-1BB monoclonal antibody suppresses antigen-induced humoral immune response in nonhuman primates. J Immunother. 2000;23:613–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellstrom KE, Mittler RS, Chen L. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med. 1997;3:682–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Kim JA, Averbook BJ, Chambers K, Rothchild K, Kjaergaard J, Papay R, Shu S. Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation. Cancer Res. 2001;61:2031–7.PubMedGoogle Scholar
  22. 22.
    Xu D, Gu P, Pan PY, Li Q, Sato AI, Chen SH. NK and CD8+ T cell-mediated eradication of poorly immunogenic B16-F10 melanoma by the combined action of IL-12 gene therapy and 4-1BB costimulation. Int J Cancer. 2004;109:499–506.PubMedCrossRefGoogle Scholar
  23. 22.
    Lane P. Role of OX40 signals in coordinating CD4 T cell selection, migration, and cytokine differentiation in T helper Th1 and Th2 cells. J Exp Med. 2000;2:201–6.CrossRefGoogle Scholar
  24. 23.
    Redmond WL, Ruby CE, Weinberg AD. The role of OX40-mediated Co-stimulation T cell activation and survival. Crit Rev Immunol. 2009;29:187–201.PubMedCrossRefGoogle Scholar
  25. 24.
    Weinberg WD, Morris NP, Kovacsovics-Bankowski M, Urba WJ, Curti BD. Science gone translational: the OX40 agonist story. Immunol Rev. 2011;244:218–31.PubMedCrossRefGoogle Scholar
  26. 26.
    Burell BE, Lu G, Li XC, Bishop DK. Costimulation prevents allograft acceptance induced by CD40-CD40L blockade. J Immunol. 2009;182:379–90.Google Scholar
  27. 25.
    Weinberg AD, Rivera MM, Prell R, Morris A, Ramstad T, Vetto JT, Urba WJ, Alvord G, Bunce C, Shields J. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol. 2000;164:2160–9.PubMedGoogle Scholar
  28. 26.
    Kjaergaard J, Tanaka J, Kim JA, Rothchild K, Weinberg A, Shu S. Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth. Cancer Res. 2000;60:5514–21.PubMedGoogle Scholar
  29. 27.
    Schaer DA, Murphy JT, Wolchok JD. Modulation of GITR for cancer immunotherapy. Curr Opin Immunol. 2012;24:217–24.PubMedCrossRefGoogle Scholar
  30. 28.
    Nocentini G, Ronchetti S, Cuzzocrea S, Riccardi C. GITR/GITRL: more than an effector T cell co-stimulatory system. Eur J Immunol. 2007;37:1165–9.PubMedCrossRefGoogle Scholar
  31. 29.
    Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002;3:135–42.PubMedCrossRefGoogle Scholar
  32. 30.
    Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, Diab A, Rizzuto G, Duan F, Perales MA, Merghoub T, Houghton AN, Wolchok JD. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One. 2010;5:1–12.CrossRefGoogle Scholar
  33. 31.
    Boczkowski D, Lee J, Pruitt S, Nair S. Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy. Cancer Gene Ther. 2009;16:900–11.PubMedCrossRefGoogle Scholar
  34. 32.
    Nishikawa H, Kato T, Hirayama M, Orito Y, Sato E, Harada N, Gnjatic S, Old LJ, Shiku H. Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling. Cancer Res. 2008;68:5948–54.PubMedCrossRefGoogle Scholar
  35. 33.
    Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, William A, Padera R, Jaklitsch MT, Shanker S, Chen TC, Korman A, Allison JP, Dranoff G. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100:4712–7.PubMedCrossRefGoogle Scholar
  36. 34.
    Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Hawarth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372–7.PubMedCrossRefGoogle Scholar
  37. 35.
    Yang JC, Hughes M, Kammula U, Royal R, Sherry R, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, Lowy I, White DE, Rosenberg SA. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825–30.PubMedCrossRefGoogle Scholar
  38. 36.
    Escudier B. Emerging immunotherapies for renal cell carcinoma. Ann Oncol. 2012;23 Suppl 8:viii35–40.PubMedCrossRefGoogle Scholar
  39. 37.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.PubMedCrossRefGoogle Scholar
  40. 38.
    Robert C, Thomas L, Bondarenko I, O’Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller Jr WH, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.PubMedCrossRefGoogle Scholar
  41. 39.
    Ribas A, Chesney JA, Gordon MS, Abernethy AP, Logan TF, Lawson DH, Chmielowski B, Glaspy JA, Lewis K, Huang B, Wang E, Hsyu PH, Gomez-Navarro J, Gerhardt D, Marshall MA, Gonzalez R. Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion. J Transl Med. 2012;10:1–6.CrossRefGoogle Scholar
  42. 40.
    Kirkwood JM, Lorigan P, Hauschild A, Robert C, McDermott D, Marshall MA, Gomez-Navarro J, Liang JQ, Bulanhagui CA. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melenoma. Clin Cancer Res. 2010;16:1042–8.PubMedCrossRefGoogle Scholar
  43. 41.
    Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31(5):616–22.PubMedCrossRefGoogle Scholar
  44. 42.
    Dolgin E. FDA okays potential blockbuster melanoma drug. Http://blogs.nature.com. N.p., 25 Mar. 2011. Web. 10 Feb. 2013.Google Scholar
  45. 43.
    Brahmer JR, Drake CG, Wollner I, Powderly J, Picus J, Sharfman W, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowry I, Topalian SL. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.PubMedCrossRefGoogle Scholar
  46. 44.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.PubMedCrossRefGoogle Scholar
  47. 45.
    Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, Xu H, Yao S, Pons A, Chen L, Pardoll DM, Brahmer JR, Topalian SL. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2013;19:462–8.PubMedCrossRefGoogle Scholar
  48. 46.
    McDermott D, Drake CG, Sznol M, Sosman JA, Smith DC, Powderly JD, Feltquate DM, Kollia G, Gupta KA, Wigginton J. A Phase I study to evaluate safety and antitumor activity of biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in Patients with RCC and other advanced refractory malignancies. J Clin Oncol 2011;29:7(Suppl): Abstract 331.Google Scholar
  49. 47.
    Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044–51.PubMedCrossRefGoogle Scholar
  50. 48.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedCrossRefGoogle Scholar
  51. 49.
    Sznol M, Hodi FS, Margolin K, McDermott DF, Ernstoff MS, Kirkwood JM, Wojtaszek C, Feltquate D, Logan T. Phase I Study of BMS-663513, a Fully Human Anti-CD137 Agonist Monoclonal Antibody, in Patients with Advanced Cancer (CA). J Clin Oncol 26: 2008 (May 20 suppl; abstr 3007).Google Scholar
  52. 50.
    Jensen SM, Maston LD, Gough MJ, Ruby CE, Redmond WL, Crittenden M, Li Y, Puri S, Poehlein CH, Morris N, Kovacsovics-Bankowski M, Moudgil T, Twitty C, Walker EB, Hu HM, Urba WJ, Weinberg AD, Curti B, Fox BA. Signaling through OX40 enhances anti-tumor immunity. Semin Oncol. 2010;37:524–32.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.School of Medicine, University of MiamiMiamiUSA

Personalised recommendations