Abstract
Simple SummaryIn 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.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 (Treg) cells play pivotal roles in hindering the anticancer immunity. Treg 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 Treg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap.
Highlights
This review will describe the mechanisms of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition, the role of Treg cells in tumorigenesis, and how anti-CTLA-4 antibodies can provoke an alteration in the expression of CTLA-4 on Treg cells while exerting anti-cancer therapeutic activity
It is necessary to inhibit interactions with both CD80 and CD86 with antibodies to optimally block the CD28-dependent proliferation of T cells in an allogenic mixed lymphocyte reaction stimulated with B lymphoblastoid cell lines
Since both CD80 and CD86 exert a positive costimulatory signal through CD28, the role played by CTLA4 in the competitive inhibition of CD28 is important for attenuating T-cell activation, thereby fine-tuning the immune response [33]
Summary
T cells with γδ expression, representing the first layer of defense, constitute nearly 2% of the T cell population in peripheral blood and secondary lymphoid organs, while they are mainly found in the epithelia of the skin, gut, lung, and other organs [15,16] Another group of innate-like T cells, called MAIT cells, constitute approximately 5% of all. Atkins et al showed that an immune checkpoint blockade of CTLA-4 improved the survival rate of renal cell carcinoma, melanoma, non-small cell lung cancer (NSCLC), and head and neck squamous cell cancer [25] This protein was the second receptor of the T-cell costimulatory ligand CD80/86 and, an immune checkpoint whose function is critical for downmodulating the immune response. This review will describe the mechanisms of CTLA-4 immune checkpoint inhibition, the role of Treg cells in tumorigenesis, and how anti-CTLA-4 antibodies can provoke an alteration in the expression of CTLA-4 on Treg cells while exerting anti-cancer therapeutic activity
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