CTLA-4 in Regulatory T Cells for Cancer Immunotherapy

SIMPLE SUMMARY: In the fight against cancer, immunotherapies have given great hope after encouraging results in clinical investigations showing complete remission in some patients with melanoma. In fact, directing the immune system against cancer has been a very innovative strategy fostered during the past three decades. Despite this fact, the disease is serious, the mortality is still very high, and only a minority of patients are responsive to immunotherapies. Therefore, there is a need for a better understanding of the molecular mechanisms of resistance to immune checkpoint inhibitors such as antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In this article, we discuss the molecular mechanism of CTLA-4 in T regulatory cell inhibition, while highlighting the knowledge gap. 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.