Unraveling the immunomodulatory role of TIM-3 in head and neck squamous cell carcinoma: implications for targeted therapy

Abstract

Head and neck squamous cell carcinoma (HNSCC) ranks among the most prevalent cancers globally, and despite improvements in treatment options such as surgery and radiotherapy, its survival rate remains low. With increased research in immunotherapy, antibodies against various immune checkpoints like programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have been shown to be effective against a wide range of tumors. Nonetheless, survival benefits gained by HNSCC patients remain limited. T-cell immunoglobulin mucin-3 (TIM-3), an emerging immune checkpoint molecule, is found to be expressed in HNSCC and is involved in shaping the tumor immune microenvironment (TIME). TIM-3 is significant in the initiation and progression of HNSCC by modulating effector T cells, innate immune cells, and other components of the immune system. Inhibiting TIM-3 can restore T cell function and enhance the immune response against HNSCC, making it a promising immunotherapeutic target for this disease. This article reviews the expression of TIM-3 in HNSCC and its immunomodulatory mechanism and briefly introduces the combined application and development prospects of TIM-3 as a potential immunotherapeutic target.

Keywords: Combination immunotherapy; Head and neck squamous cell carcinoma; Human papillomavirus; T-cell immunoglobulin mucin-3; Tumor immune microenvironment.

Fig. 1

(By Figdraw). Structure of Tim-3 and its role with ligands. + : express promotion −: express inhibition. The structure of Tim-3 includes an immunoglobulin domain, a mucin-like domain, a transmembrane region composed of a hydrophobic amino acid sequence, and a cytoplasmic tail. Tim-3 has four ligands: binding to Gal-9 induces apoptosis in Th1 cells and inhibits IFN-γ production; interaction with CEACAM1 suppresses T cell function; binding to HMGB1 weakens nucleic acid-mediated innate immune responses; and interaction with PtdSer promotes the phagocytosis of apoptotic cells. When Tim-3 is unbound to ligands, BAT3 associates with its cytoplasmic tail to recruit LCK, thereby maintaining T cell function

Fig. 2

(By Figdraw). Expression and immunomodulation of Tim-3 in the immune microenvironment of HNSCC. + : express promotion −: express inhibition × : express blocking. In the immune microenvironment of HNSCC, TIM-3 mainly affects effector T cells and innate immune cells to achieve immunosuppression. TIM-3 reduces the anti-tumor activity of CD8 + T cells and, in combination with Gal-9, induces apoptosis and downregulates the immune response of Th1 cells. Tregs are activated to inhibit CD8 + T cell activation and suppress NKs. In addition, Treg cells inhibit the activation of CD8 + T cells by producing TGF-β and IL-10.TIM-3 expression on Tregs enhances their inhibitory function. MDSCs are often associated with HNSCC tumor progression.TIM-3 interacts with Gal-9 and promotes MDSC production. CXCL1 induces MDSCs recruitment by binding to CXCR2, a receptor expressed by MDSCs, and blocking TIM-3 downregulates CXCL1, thereby reducing MDSCs. TIM-3 is expressed on DCs and is involved in immune evasion by inhibiting DC activation and T cell initiation. Expression of TIM-3 on macrophages promotes M2 polarization, which promotes tumor growth, whereas stimulation of TLR-3 signaling biases macrophages toward an MI phenotype, which inhibits tumor progression. TIM-3 induces downregulation of Bat3 in tumor-infiltrating NKs when it is not bound to ligands, which promotes cytotoxicity by inhibiting TIM-3 signaling. However, TIM-3 could mediate NK cell failure when bound to Gal-9 or CEACAM1.

Fig. 3

(By Biorender). Immunologic microenvironment of HPV⁺ HNSCC vs HPV⁻ HNSCC. In HNSCC patients, the immune microenvironment varied according to HPV status. Compared with HPV⁻ HNSCC, HPV⁺ HNSCC patients had a stronger immune response, with significantly increased CTL expression and greater production of cytokines (IFN-γ, IL-17) in their tumor tissues; higher levels of Tregs expression; Gal-9 was highly expressed on CD4⁺ T cells; and the number of mDCs, pDCs, monocytes/macrophages, and chemokines was also higher; PD1 mRNA expression was significantly higher, while Cox-2 mRNA expression was significantly lower.