Diffuse large B-cell lymphoma: the significance of CD8 + tumor-infiltrating lymphocytes exhaustion mediated by TIM3/Galectin-9 pathway

• Published in: Journal of translational medicine 2024-02, Vol.22 (1), p.174-14, Article 174
• Main Authors: Zhu, Qiqi, Yang, Yiming, Chen, Kexin, Zhang, Qiaoyu, Huang, Yifan, Jian, Shunhai
• Format: Article
• Language: English
• Subjects: Analysis; B-cell lymphoma; Cancer; Care and treatment; CD8 antigen; CD8+ tumor-infiltrating lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chemotherapy; Diagnosis; Diffuse large B-cell lymphoma; Exhaustion; Galectin-9; Galectins - metabolism; Genes; Genetic aspects; Hepatitis A Virus Cellular Receptor 2 - metabolism; Humans; Immune checkpoint; Immune checkpoint inhibitors; Immunohistochemistry; Immunotherapy; Ligands; Lymphatic system; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphocytes, Tumor-Infiltrating; Lymphoma; Lymphoma, Large B-Cell, Diffuse - pathology; Macrophages; Medical prognosis; Medical records; Non-Hodgkin's lymphomas; Patient outcomes; Polymerase chain reaction; Principal components analysis; Quality control; Reverse transcription; Ribonucleic acid; RNA; RNA sequencing; Signal transduction; Single-cell RNA sequencing; Software; TIM3/Galectin-9 pathway; Tumor Microenvironment; Tumor-infiltrating lymphocytes; γ-Interferon
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-024-05002-3

Overexpression of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is related to the exhaustion of CD8 tumor-infiltrating lymphocytes (TILs) in diffuse large B-cell lymphoma (DLBCL). However, the mechanism of TIM3-mediated CD8 TILs exhaustion in DLBCL remains poorly understood. Therefore, we aimed to clarify the potential pathway involved in TIM3-mediated CD8 TILs exhaustion and its significance in DLBCL. The expression of TIM3 and its correlation with CD8 TILs exhaustion, the key ligand of TIM3, and the potential pathway of TIM3-mediated CD8 TILs exhaustion in DLBCL were analyzed using single-cell RNA sequencing and validated by RNA sequencing. The biological significance of TIM3-related pathway in DLBCL was investigated based on RNA sequencing, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction data. Finally, the possible regulatory mechanism of TIM3-related pathway in DLBCL was explored using single-cell RNA sequencing and RNA sequencing. Our results demonstrated that CD8 TILs, especially the terminally exhausted state, were the major clusters that expressed TIM3 in DLBCL. Galectin-9, mainly expressed in M2 macrophages, is the key ligand of TIM3 and can induce the exhaustion of CD8 TILs through TIM3/Galectin-9 pathway. Meanwhile, high TIM3/Galectin-9 enrichment is related to immunosuppressive tumor microenvironment, severe clinical manifestations, inferior prognosis, and poor response to CHOP-based chemotherapy, and can predict the clinical efficacy of immune checkpoint blockade therapy in DLBCL. Furthermore, the TIM3/Galectin-9 enrichment in DLBCL may be regulated by the IFN-γ signaling pathway. Our study highlights that TIM3/Galectin-9 pathway plays a crucial role in CD8 TILs exhaustion and the immune escape of DLBCL, which facilitates further functional studies and could provide a theoretical basis for the development of novel immunotherapy in DLBCL.