Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy.

Simple Summary: Immunotherapy has transformed the treatment of advanced cancers by leveraging patients' immune system in attacking tumor cells. Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T-cells (Tregs) that suppresses the function of tumor-reactive T-cells responsible for eliminating cancer cells. CTLA-4-targeting agents can release the "brakes" off the immune system to promote anti-tumor immune responses. Anti-CTLA-4 has been used to treat various solid cancers for over a decade; however, its exact mechanism(s) of action is still widely debated. There is a need to understand the fundamental mechanism(s) of anti-CTLA-4 function to employ strategies to improve its therapeutic efficacy and develop the next-generation of anti-CTLA-4 antibodies. This article is an in-depth analysis of the proposed mechanisms of anti-CTLA-4 therapy and its newfound uses in cancer treatment. Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T-cells (Tregs) that can inhibit the activation of effector T-cells. Anti-CTLA-4 therapy can confer long-lasting clinical benefits in cancer patients as a single agent or in combination with other immunotherapy agents. However, patient response rates to anti-CTLA-4 are relatively low, and a high percentage of patients experience severe immune-related adverse events. Clinical use of anti-CTLA-4 has regained interest in recent years; however, the mechanism(s) of anti-CTLA-4 is not well understood. Although activating T-cells is regarded as the primary anti-tumor mechanism of anti-CTLA-4 therapies, mounting evidence in the literature suggests targeting intra-tumoral Tregs as the primary mechanism of action of these agents. Tregs in the tumor microenvironment can suppress the host anti-tumor immune responses through several cell contact-dependent and -independent mechanisms. Anti-CTLA-4 therapy can enhance the priming of T-cells by blockading CD80/86-CTLA-4 interactions or depleting Tregs through antibody-dependent cellular cytotoxicity and phagocytosis. This review will discuss proposed fundamental mechanisms of anti-CTLA-4 therapy, novel uses of anti-CTLA-4 in cancer treatment and approaches to improve the therapeutic efficacy of anti-CTLA-4. [ABSTRACT FROM AUTHOR]