Immune checkpoints and cancer development: Therapeutic implications and future directions

Over the past few decades, different inhibitory receptors have been identified, which have played prominent roles in reducing anti-tumor immune responses. The role of immune checkpoint inhibitors in cancer was revealed by critical blockade of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) checkpoints. Immune checkpoint inhibitors, including anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (Atezolizumab, avelumab, and duravulumab), and anti-CTLA-4 (ipilimumab, tremelimumab), are currently FDA-approved treatment options for a broad range of cancer types. However, regarding immunotherapy advances in recent years, most studies have been focused on finding the antibodies against other inhibitory immune checkpoints in the tumor microenvironment such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin, and mucin domain 3 (TIM-3), B7-homolog 3 (B7-H3), V-domain immunoglobulin-containing suppressor of T-cell activation (VISTA), diacylglycerol kinase-α (DGK-α), T cell immunoglobulin and ITIM domain (TIGIT), and B and T lymphocyte attenuator (BTLA). This immune checkpoint exerts differential inhibitory impacts on various types of lymphocytes. The suppression of immune responses demonstrates a surprising synergy with PD-1. Therefore, most antibodies against these immune checkpoints are undertaking clinical trials for cancer immunotherapy of advanced solid tumors and hematologic malignancies. In this review, we will summarize recent findings of immune checkpoint and the role of monoclonal antibodies in cancer immunotherapy targeting these receptors.