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CTLA-4

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint receptor that negatively regulates the immune response. Blocking CTLA-4 may directly restore T-cell activation, reverse regulatory T cell (Treg)-
driven T-cell suppression, and lead to long-term antitumor immunity. Research is ongoing to further optimize CTLA-4 blockade.

Expression and normal function

CTLA-4 is an immune checkpoint receptor expressed on the surface of activated
T cells^1,2

Binding of CTLA-4 on cytotoxic T cells to CD80/86 on antigen-presenting cells (APCs) inhibits T-cell activation³

Activation is initiated when an antigen is presented to the T-cell receptor (TCR) by the major histocompatibility complex (MHC) on APCs³
Completion of the activation process requires a second signal.^4-6 This occurs when CD28, the primary costimulatory receptor on T cells, binds to CD80 and CD86 on APCs to maintain immune response^2,3

When CTLA-4 is upregulated, it competes with CD28 for binding to CD80/86. CTLA-4 binding inhibits T-cell activation and preserves balance when the immune system is overactive^6-8
CTLA-4 signaling on Tregs leads to suppression of the immune response⁹

Tregs play a key role in counterbalancing excessive immune activation by inhibiting the activation and function of other immune cells^10,11
Continuous expression of CTLA-4 on Tregs is critical for their suppressive activity^9,12

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Role in cancer

In cancer, tumor cells leverage the CTLA-4 pathway to decrease T-cell activation, proliferation, and effector function^8,13
CTLA-4 signaling in cancer also diminishes the ability of memory T cells to sustain a response, damaging a key element of durable immunity^8,13

Memory T cells, which have an almost indefinite lifespan, provide long-term immunity.¹⁴ When exposed to a tumor antigen, memory T cells can recognize and immediately mount an immune response against the tumor.¹⁵ In cancer, these cells are associated with long-term survival and low risk of tumor recurrence^16,17
CTLA-4 signaling in cancer reduces proliferation of memory T cells^8,13

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Preclinical evidence

According to preclinical data, CTLA-4–specific antibodies can restore an immune response by increasing the activation, accumulation, function, and survival of T cells and memory T cells, and by depleting Tregs in the tumor microenvironment^8,18,19
However, CTLA-4 inhibition may also lead to immune attack of healthy cells.²⁰ CTLA-4 inhibition, either alone or in combination with other checkpoint pathways, is currently being researched to optimize the antitumor response²¹

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Optimizing CTLA-4 blockade: Treg depletion

One approach aims to regulate the degree of immune activity using non-fucosylated antibodies to deplete Tregs

Poor prognosis in various cancers is associated with the presence of Tregs^22,23
Unlike fucosylated antibodies, non-fucosylated antibodies have a modified Fc region, which enhances binding to Fc receptors on immune cells that mediate antibody-dependent cellular cytotoxicity (ADCC).²⁴ The enhanced binding leads to increased antibody activity that depletes Tregs and results in greater T-cell activation^19,24
Mouse models have shown that increased Treg depletion can improve
cytotoxic T-cell activation and antitumor activity²⁵

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Optimizing CTLA-4 blockade: increasing specificity

Another approach uses pro-antibodies that can improve CTLA-4–blockade specificity by reducing antibody binding outside of the tumor microenvironment, sparing healthy tissues^26,27

These antibodies are primarily active at the tumor site because they have been masked with a peptide that is removed by enzymes that are either highly expressed by or only present on tumor cells²⁶
Preclinical data indicate that limiting antibody binding in the tumor microenvironment may prevent the immune system from attacking healthy cells, yet still enable an antitumor response^27,28
Novel approaches for optimizing CTLA-4 blockade’s ability to restore the immune response are currently under investigation

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How can CTLA-4 play a role in long-term immunity?

Learn more about CTLA-4 and memory T-cell activity

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REFERENCES–CTLA-4

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, Grasmere 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. 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. 9. Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271-275. 10. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12(4):252-264. 11. Melero I, Berman DM, Aznar MA, Koran AJ, Pérez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457-472. 12. 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. 13. 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. 14. Lau LL, Jamieson BD, Somasundaram T, Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994;369(6482):648-652. 15. 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. 16. 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. 17. 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. 18. 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. 19. 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. 20. Amos SM, Duong CPM, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011; 118(3):499-509. 21. Beavis PA, Henderson MA, Giuffrida L, et al. Dual PD-1 and CTLA-4 checkpoint blockade promotes antitumor immune responses through CD4Foxp3 cell-mediated modulation of CD103 dendritic cells. Cancer Immunol Res. 2018;6(9):1069-1081. 22. 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. 23. 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. 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. doi:o10.1038/s41598-017-11886-7. 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.