Suppression of non-muscle myosin II boosts T cell cytotoxicity against tumors

Increasing evidence highlights the importance of immune mechanoregulation in establishing and sustaining tumor-specific cytotoxicity required for desirable immunotherapeutic outcomes. However, the molecular connections between mechanobiological inputs and outputs and the designated immune activities...

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Bibliographic Details
Published in:Science advances 2024-11, Vol.10 (44), p.eadp0631
Main Authors: Yang, Yingyun, Wen, Dahan, Lin, Feng, Song, Xiaowei, Pang, Ruiyang, Sun, Weihao, Yu, Donglin, Zhang, Ziyi, Yu, Tao, Kong, Jie, Zhang, Lei, Cao, Xinyuan, Liao, Wanying, Wang, Dingding, Yang, Qianyi, Liang, Junbo, Zhang, Ning, Li, Kailong, Xiong, Chunyang, Liu, Yuying
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Cell Line, Tumor
Cytotoxicity, Immunologic
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Mice
Myosin Type II - metabolism
Neoplasms - immunology
Neoplasms - metabolism
Neoplasms - pathology
Neoplasms - therapy
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Tumor Microenvironment - immunology
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Summary:Increasing evidence highlights the importance of immune mechanoregulation in establishing and sustaining tumor-specific cytotoxicity required for desirable immunotherapeutic outcomes. However, the molecular connections between mechanobiological inputs and outputs and the designated immune activities remain largely unclear. Here, we show that partial inhibition of non-muscle myosin II (NM II) augmented the traction force exerted by T cells and potentiated T cell cytotoxicity against tumors. By using T cells from mice and patients with cancer, we found that NM II is required for the activity of NKX3-2 in maintaining the expression of ADGRB3, which shapes the filamentous actin (F-actin) organization and ultimately attributes to the reduced traction force of T cells in the tumor microenvironment. In animal models, suppressing the NM II-NKX3-2-ADGRB3 pathway in T cells effectively suppressed tumor growth and improved the efficacy of the checkpoint-specific immunotherapy. Overall, this work provides insights into the biomechanical regulation of T cell cytotoxicity that can be exploited to optimize clinical immunotherapies.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adp0631