Activated CTLA‐4‐independent immunosuppression of Treg cells disturbs CTLA‐4 blockade‐mediated antitumor immunity

Abstract

Combination therapy with anti‐cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) and anti‐programmed death‐1 (PD‐1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4 + T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA‐4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg‐cell‐mediated immunosuppressive functions, suppressing antigen‐presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti‐CTLA‐4 mAb with antibody‐dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that CTLA‐4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg‐cell proliferation in mouse models. CTLA‐4 blockade also augmented CTLA‐4‐independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor‐infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg‐cell depletion to achieve tumor regression in response to CTLA‐4 blockade therapies.

Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point?

“…In addition, TCR/CD28 costimulation can induce cytotoxic T-lymphocyte antigen-4 (CTLA-4). The high expression of CTLA-4 on Tregs supports its immunosuppressive activity, so anti-CTLA-4 antibody has been developed as an immune checkpoint inhibitor ( 38 , 39 ).…”

Mechanisms of esophageal cancer metastasis and treatment progress

“…Furthermore, CTLA-4 on Tregs has a higher affinity for CD80/CD86 on APCs compared to CD28 molecules on T cells. This competitive binding of CTLA-4 to CD80/CD86 inhibits CD28 stimulation on T cells and modulates APC activation ( 108 – 110 ) ( Figure 2 ).…”

Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

“…It has been reported to participate in regulating T-cell apoptosis, regulating the expression of cytokines, and inhibiting the proliferation of T cells, thereby exerting an immunosuppressive effect. 17,18 Furthermore, CD28, a homologous receptor with CTLA-4, is expressed in CD8 + and CD4 + T cells. 19 However, CTLA-4 has the opposite effect on the activation of T cells, which is mainly caused by competing ligand binding with CD28.…”

“…21,22 Attractively, the interaction affinity between CTLA-4 and its ligands is greater than that between CTLA-4 and CD28; the affinity between CTLA-4 and CD80 is the largest, and that between CTLA-4 and CD28-CD86 is the weakest. 18,23 Therefore, it proposes the concept that CTLA-4 competes against CD28 for ligands, thus serving as an antagonist of CD28-mediated costimulation 24 (Figure 1). Importantly, the expression of CTLA-4 is strongly upregulated in HCC patients.…”

“…Cytotoxic T lymphocyte antigen 4 (CTLA‐4) is another ICP that inhibits T‐cell function and is mainly expressed on B lymphocytes and activated CD8+ and CD4+ T lymphocyte surfaces. It has been reported to participate in regulating T‐cell apoptosis, regulating the expression of cytokines, and inhibiting the proliferation of T cells, thereby exerting an immunosuppressive effect 17,18 . Furthermore, CD28, a homologous receptor with CTLA‐4, is expressed in CD8 + and CD4 + T cells 19 .…”