Immune checkpoint TIM-3 in tumor immunotherapy

Abstract

Over the past decade, immunotherapy has emerged as a pivotal therapeutic strategy in cancer treatment. Immune checkpoint inhibitors (ICIs), such as CTLA-4 and PD-1 monoclonal antibodies, have demonstrated remarkable clinical efficacy in different types of cancer. However, the overall success rate of immune checkpoint therapies remains low. Investigating alternative immune checkpoint molecules is imperative. T-cell immunoglobulin and mucin-containing molecule-3 (TIM-3), which is expressed in T cells, natural killer (NK) cells, macrophages, and dendritic cells, has gained recognition as a promising candidate for tumor immunotherapy. Targeting TIM-3 represents a promising approach for cancer immunotherapy, particularly through the rational design of novel combination therapies with other ICIs. In this review, we present a comprehensive summary of the research advancements concerning the role of TIM-3 in regulating immune responses in different cell types and explore theoretical frameworks for targeting TIM-3 to achieve more effective immunotherapeutic breakthroughs.

1. Introduction

Immunotherapy involving immune checkpoint inhibitors (ICIs) has become a critical approach for combating cancer. The United States Food and Drug Administration (FDA) has approved anti-CTLA-4 monoclonal antibodies (mAbs) and anti-PD-1 mAbs for the treatment of melanoma and non-small cell lung carcinoma (NSCLC) [1–3]. Although ICI therapies have improved survival compared with traditional cancer treatments for various cancer types, only 10%-30% of patients benefit from these therapies in most cancer types [4]. Therefore, it is imperative to identify new immune checkpoint molecules and elucidate their underlying mechanisms to further advance cancer immunotherapy.

T-cell immunoglobulin and mucin-containing molecule-3 (TIM-3) was initially identified in 2002 and is expressed on CD4+ T helper 1 (Th1) and CD8+ cytotoxic T lymphocytes (CTLs) [5]. Subsequent studies revealed that TIM-3 is also expressed on the surface of activated natural killer (NK) cells [6], Th17 cells [7], gamma delta (γδ) T cells [8–11], regulatory T cells (Tregs) [12], macrophages [5], dendritic cells (DCs) [13], and mast cells [14]. TIM-3 belongs to the TIM gene family, which in humans comprises three members: TIM-1, TIM-3, and TIM-4. These proteins are encoded by the genes HAVCR1, HAVCR2, and TIMD4, respectively [15]. TIM-3 consists of an immunoglobulin variable (IgV) domain, a mucin stalk domain, a single transmembrane domain, and a cytoplasmic tail domain [16]. It has at least four ligands: galectin-9 (Gal-9), carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), high-mobility group protein B1 (HMGB1), and phosphatidylserine (PtdSer), all of which interact with the TIM-3 IgV domain. The interaction between TIM-3 and its ligands mediates the suppression of anti-tumor immune responses [17]. Gal-9, the first ligand identified, induces apoptosis in Th1 cells and negatively regulates Th1 cell immunity [18,19]. Furthermore, the TIM-3/CEACAM1 interaction induces T cell exhaustion [20]. Numerous preclinical studies across various tumor types have demonstrated that TIM-3 blockade can inhibit tumor progression, particularly when combined with PD-1/PD-L1 blockade [21,22]. Therefore, targeting TIM-3, either in combination with other ICIs or through integrating TIM-3 inhibition with novel immunotherapeutic strategies that activate cancer-specific T-cell stimulatory molecules, shows great promise for advancing therapeutic approaches with enduring clinical efficacy.