CTLA-4 in Regulatory T Cells for Cancer Immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are currently limited to a minority of patients and there is a need to develop a better understanding of the basic molecular mechanisms and functions of pivotal immune regulatory molecules. Immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and regulatory T (T_reg) cells play pivotal roles in hindering the anticancer immunity. T_reg cells suppress antigen-presenting cells (APCs) by depleting immune stimulating cytokines, producing immunosuppressive cytokines and constitutively expressing CTLA-4. CTLA-4 molecules bind to CD80 and CD86 with a higher affinity than CD28 and act as competitive inhibitors of CD28 in APCs. The purpose of this review is to summarize state-of-the-art understanding of the molecular mechanisms underlining CTLA-4 immune regulation and the correlation of the ICI response with CTLA-4 expression in T_reg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap.

Keywords: CD28; CTLA-4; Treg cells; antigen-presenting cells; immune checkpoint inhibitors.

Figure 1

Regulatory T (T_reg) cells inhibit antigen-presenting cells (APC) by three main mechanisms: (1) Depleting immune-stimulating cytokines; (2) producing immunosuppressive cytokines (e.g., TGF-β, IL-10, and IL-35); and (3) constitutively expressing CTLA-4, which blocks the priming and activation of naïve CD4+ T (T_conv) cells to APCs.