CTLA-4 Prevents Long-Term Immune Responses

CTLA-4 prevents T-cell activation

Cytotoxic T-Lymphocyte-associated Antigen 4 (CTLA-4) is an immune checkpoint receptor expressed on the surface of T cells, and is one of the most studied checkpoint pathways.^1,2 In the normal immune response, exposure to antigens initiates the process of T-cell activation.³ However, antigen presentation alone is not sufficient to induce an immune response.⁴ A second signal either allows activation to proceed or stops the process from continuing.^5,6 CD28 maintains activation and initiates an immune response.⁵ CTLA-4 competes with CD28 and prevents activation, preserving balance when the immune system is overactive.^6,7 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

Tumor cells utilize the CTLA-4 pathway to suppress initiation of an immune response, resulting in decreased T-cell activation and ability to proliferate into memory T cells.^9,10

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

With an almost indefinite lifespan, memory T cells provide long-term immunity.¹¹ 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 immunity

Preclinical data demonstrate that treatment with antibodies specific for CTLA-4 can restore an immune response through two mechanisms: increased accumulation and survival of memory T cells, as well as depletion of Tregs.^16-19

Research to further understand these pathways is ongoing.

Previous PD-1 Pathway

Next Additional Effector T Cell Pathways

References

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