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

Abstract

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.

Keywords: ADCC/P; CD28 costimulation; CTLA-4; FOXP3; Tregs; anti-CTLA-4; immunotherapy; ipilimumab.

Figure 1

Enhancing the priming of effector T-cells by blockading CD80/86-CTLA-4 interactions. High expression of CTLA-4 on Tregs contributes to their immunosuppressive phenotype. Effector T-cells can express CTLA-4 transiently after T-cell activation. CTLA-4 engagement with CD80/86 on antigen-presenting cells inhibits CD28 costimulation that is required for T-cell activation and the upregulation of ICOS. Anti-CTLA-4 binds to CTLA-4 and inhibits CD80/86-CTLA-4 interactions to increase the activation of anti-tumor effector T-cells. T-cell activation results in clonal expansion and the employment of effector mechanisms that facilitate anti-tumor immune responses.

Figure 2

Antibody-mediated Treg depletion. Anti-CTLA-4 bound to Tregs can engage with FcγRs expressed on innate cells to deplete Tregs. Macrophages and natural killer cells can deplete Tregs through antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC). Depleting intra-tumoral Tregs promotes anti-tumor immune responses by transforming the immunosuppressive nature of the tumor microenvironment into a pro-inflammatory microenvironment. This is enabled by indirectly increasing anti-tumor effector T-cells’ activation, infiltration, and effector functions.

Figure 3

Alteration of Treg metabolism and plasticity. Anti-CTLA-4 allows CD28 on Tregs to engage with CD80/86 on antigen-presenting cells. Costimulatory signaling shifts the metabolism of Tregs from oxidative phosphorylation (OXPHOS) to glycolysis. Increasing glycolysis can functionally and phenotypically destabilize the immunosuppressive nature of Tregs. Tregs can adopt the pro-inflammatory characteristics of Th1 and Th17 cells to contribute to anti-tumor immune responses.