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CTLA-4: Inhibits Long-term Immune Responses

CTLA-4 inhibits T-cell activation

CTLA-4 inhibits T-cell activation 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 an 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. Unlike fucosylated antibodies, non-fucosylated antibodies have a modified Fc region, enabling enhanced binding to Fc receptors on immune cells that mediate antibody-dependant cellular cytotoxicity (ADCC).23 This enhanced binding leads to increased antibody activity, leading to Treg depletion and subsequently greater T-cell activation.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, thereby sparing healthy tissues.26,27 Antibodies that have been masked with a peptide, or pro-antibodies, can have the peptide 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.


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ONCUS1702354-07-01  11/18