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CTLA-4: Inhibits Long-term Immune Responses

CTLA-4 inhibits T-cell activation

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint receptor expressed on the surface of activated T cells.1,2 In the normal immune response, T-cell activation is initiated when antigen is presented to the T-cell receptor (TCR) by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs).3 Antigen presentation alone, however, is not sufficient to induce an immune response.4 Completing the activation process requires a second signal.5,6 To maintain activation of an immune response, CD28—the primary costimulatory receptor on T cells—binds to CD80 and CD86 on APCs.2,3,5 When CTLA-4 is upregulated, it competes with CD28 and has a greater affinity for CD80/86. Binding of CTLA-4 to CD80/86 inhibits T-cell activation, preserving balance when the immune system is overactive.6,7


CTLA-4 drives effector-cell suppression by Tregs

CTLA-4 can also be found on regulatory T cells (Tregs), where it is a key driver of their ability to suppress T-cell activity.8 Tregs are suppressor cells that inhibit the activation and function of other immune cells. They play a key role in counterbalancing excessive immune activation.9,10 Continuous expression of CTLA-4 on Tregs is critical for their suppressive activity.8,11 Poor prognosis in various cancers is associated with the presence of Tregs.12,13


Long-term immunity is impaired by CTLA-4, among other mechanisms

Tumor cells utilize the CTLA-4 pathway to suppress initiation of an immune response, resulting in decreased T-cell activation and a reduced ability to proliferate into memory T cells.14,15

With an almost indefinite lifespan, memory T cells provide long-term immunity.16 After they have been exposed to tumor antigen, memory T cells can recognize and immediately mount an immune response against the tumor.12 The presence of memory T cells is associated with long-term survival and low risk of tumor recurrence in cancer.13,14

CTLA-4 signaling diminishes the ability of memory T cells to sustain a response, damaging a key element of durable immunity.15


Inhibition of CTLA-4 restores antitumor immunity

Preclinical data demonstrate that antibodies specific for CTLA-4 can restore an immune response through the increased accumulation, function, and survival of T cells and memory T cells, as well as the depletion of Tregs.14,20,21 Although inhibition of CTLA-4 can improve the antitumor response, it may also lead to immune attack of healthy cells.22 Novel approaches to enhance either the degree or specificity of immune activation with CTLA-4 blockade are under investigation.

One recent approach to regulate the degree of immune activity is to increase the depletion of Tregs. A specific type of CTLA-4 antibody with a modified Fc region, known as a non-fucosylated antibody, can bind to Tregs, identifying them for elimination by other immune cells.21,23,24 As shown in mouse models, the increased depletion of Tregs can improve cytotoxic T-cell activation and antitumor activity.25

Another approach aims to improve the specificity of CTLA-4 blockade by reducing antibody binding outside of the tumor microenvironment.27 Antibodies that have been masked with a protein, or pro-antibodies, can have the protein removed by enzymes that are either highly expressed by or only present on tumor cells. Pro-antibodies are therefore active primarily at the tumor site.23,26 Preclinical data indicate that limiting antibody binding to the tumor microenvironment may prevent immune attack of healthy cells, yet still enable an antitumor response.23,27,28


Research to further understand these pathways is ongoing.

References

1. Perkins D, Wang Z, Donovan C, et al. Regulation of CTLA-4 expression during T cell activation. J Immunol. 1996;156(11):4154-4159. 2. Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. 2015. doi:10.3389/fimmu.2015.00418. 3. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227-242. 4. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734-1736.
5. Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991;173(3):721-730.
6. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1(5):405-413. 7. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541-547. 8. Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271-275. 9. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 10. Melero I, Berman DM, Aznar MA, Korman AJ, Pérez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457-472. 11. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen
4. J Exp Med. 2000;192(2):303-309. 12. Saito T, Nishikawa H, Wada H, et al. Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med. 2016;22(6):679-684. 13. Tao H, Mimura Y, Aoe K, et al. Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer. 2012;75(1):95-101. 14. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. 15. Chambers CA, Sullivan TJ, Truong T, Allison JP. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells.
Eur J Immunol. 1998;28(10):3137-3143. 16. Lau LL, Jamieson BD, Somasundaram T, Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994;369(6482):648-652. 17. Viega-Fernandes H, Walter U, Bourgeois C, McLean A, Rocha B. Response of naïve and memory CD8+ T cells to antigen stimulation in vivo. Nat Immunol. 2000;1(1):47-53. 18. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960-1964. 19. Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298-306.
20. Pedicord VA, Montalvo W, Leiner IM, Allison JP. Single dose of anti–CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci U S A. 2011;108(1):266-271. 21. Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J Exp Med. 2013;210(9):1695-1710. 22. Amos SM, Duong CPM, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118(3):499-509. 23. Korman AJ, Engelhardt J, Loffredo J, et al. Next generation anti–CTLA-4 antibodies. Oral presentation at AACR 2017. Abstract #SY09-01.
24. Satoh M, Iida S, Shitara K. Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies. Expert Opin Biol Ther. 2006;6(11):1161-1173. 25. Selby MJ, Engelhardt JJ, Quigley M, et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1(1):32-42. 26. Chen I-J, Chuang C-H, Hsieh Y-C, et al. Selective antibody activation through protease-activated pro-antibodies that mask binding sites with inhibitory domains. Sci Rep. 2017;7(1):11587. 27. Tuve S, Chen B-M, Liu Y, et al. Combination of tumor site–located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses. Cancer Res. 2007;67(12):5929-5939. 28. Fransen MF, van der Sluis TC, Ossendorp F, Arens R, Melief CJM. Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects. Clin Cancer Res. 2013;19(19):5381-5389.

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