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.                                      
  • 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 activation.3
      • Activation is initiated when an antigen is presented to the T-cell receptor (TCR) by the major histocompatibility complex (MHC) on APCs.3
      • 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 response.9
      • 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
  • 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
  • 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 response.21
  • 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 activity.25
  • 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 cells.26
    • 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.

View areas of research related to CTLA-4


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  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.
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  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.
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