Preclinical evaluation of TIGIT as a target to enhance efficacy and mitigate T cell exhaustion in multiple myeloma following BCMA-CAR-T therapy

作者：Yuan Xia, Zhu Jian-feng, Rui Guo, Xuxing Shen, Min Shi, Na Shen, Lei Fan, Lijuan Chen · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-08203-w · 被引用次数：5 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Multiple Myeloma Research and Treatments

Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has achieved notable efficacy in relapsed/refractory multiple myeloma (RRMM), yet most patients eventually relapse, highlighting the need to elucidate mechanisms of resistance. In this study, we investigated the role of TIGIT in resistance to BCMA-CAR-T therapy. Tumor-infiltrating T cells from RRMM patients receiving BCMA-CAR-T therapy were analyzed by single-cell RNA sequencing, and immune checkpoint expression was further assessed by flow cytometry. Functional assays, including luciferase-based cytotoxicity, CD107a degranulation, CFSE proliferation, and CD45RO/CD62L phenotyping, were performed to investigate the effects of TIGIT inhibition through knockout or anti-TIGIT monoclonal antibodies (mAbs). In a humanized immune cell-reconstituted mouse model, TIGIT blockade was further evaluated for its effects on tumor growth and T cell exhaustion. T cells from patients with early relapse exhibited higher TIGIT expression than those from patients with durable responses, and elevated TIGIT levels were correlated with increased tumor burden and poor prognosis. While TIGIT blockade exerted limited effects on CAR-T function in vitro, it markedly enhanced CAR-T proliferation, mitigated T cell exhaustion, and improved antitumor efficacy in vivo, particularly when mediated by anti-TIGIT mAbs. Transcriptomic profiling further revealed that TIGIT modulates CAR-T activity by regulating cytokines and...