Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors

Abstract

The differentiation, survival, and effector function of tumor-specific CD8+ cytotoxic T cells lie at the center of antitumor immunity. Due to the lack of proper costimulation and the abundant immunosuppressive mechanisms, tumor-specific T cells show a lack of persistence and exhausted and dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, and LAG-3, contribute to dysfunctional CTLs and failed antitumor immunity. These coinhibitory receptors are collectively called immune checkpoint receptors (ICRs). Immune checkpoint inhibitors (ICIs) targeting these ICRs have become the cornerstone for cancer immunotherapy as they have established new clinical paradigms for an expanding range of previously untreatable cancers. Given the nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies are being tested to bring synergistic benefits to patients. In this review, we summarize the mechanisms of several emerging ICRs, including VISTA, TIGIT, TIM-3, and LAG-3, and the preclinical and clinical data supporting combinatorial strategies to improve existing ICI therapies.

LRIG1 engages ligand VISTA and impairs tumor-specific CD8 + T cell responses

“…Previous studies in preclinical models and human cancer tissues have shown that VISTA is highly expressed within the TME, either on tumor-associated myeloid APCs or aberrantly expressed on tumor cells (12)(13)(14)(30)(31)(32). The abundance of VISTA in tumor tissues indicates the potential role of trans-VISTA in driving T cell dysfunction.…”

“…V domain immunoglobulin suppressor of T cell activation (VISTA)-also known as Dies1, Gi24, PD-1H, or DD1α-is a B7 family immune checkpoint protein and a next-generation immunotherapy target (9)(10)(11)(12)(13)(14). Previous studies have indicated that VISTA inhibits T cell activation by two modes of action: VISTA expressed on antigen-presenting cells (APCs) mediates the "trans" suppression by engaging its cognate receptor on T cells, whereas VISTA expressed on T cells elicits "cis" intrinsic suppression (9,11,15).…”

Cutting-Edge Therapies for Lung Cancer

“…Despite the absence of FDA-approved therapies targeting TIM-3, the advancement of novel TIM-3 inhibitors is rapidly evolving in lung cancer. Numerous TIM-3-specific antibodies, such as cobolimab, sabatolimab (MBG453), BMS-986258, AZD7789, INCAGN02390, etc., are under investigation [ 104 ].…”

TIM-3, LAG-3, or 2B4 gene disruptions increase the anti-tumor response of engineered T cells

“…Strategies to tailor inhibitory receptor disruption in tumor-specific cellular products have been proposed to overcome these limitations, but are mainly focused on PD-1- or CTLA-4- disrupted cells tested in short-term anti-tumor responses ( 23 – 31 ). Here, we selected TIM-3, LAG-3 and 2B4, three inhibitory receptors frequently expressed by T cells in several cancer types and involved in resistance to immunotherapy ( 32 , 33 ), and we exploited the multiplexicity of CRISPR/Cas9 with lentiviral vectors to simultaneously redirect T cell specificity and disrupt genes encoding for TIM-3, LAG-3, or 2B4, within a protocol able to expand long-living early differentiated T SCM ( 34 ). With this approach, we investigated the relative contribution of distinct IR knocked-out in tumor specific cellular products chronically challenged by multiple myeloma cells.…”