Epigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T cell-mediated cytotoxicity in lung cancer

• Published in: Nature communications Vol. 12; no. 1; pp. 2163 - 18
• Main Authors: Weng, Rueyhung R., Lu, Hsuan-Hsuan, Lin, Chien-Ting, Fan, Chia-Chi, Lin, Rong-Shan, Huang, Tai-Chung, Lin, Shu-Yung, Huang, Yi-Jhen, Juan, Yi-Hsiu, Wu, Yi-Chieh, Hung, Zheng-Ci, Liu, Chi, Lin, Xuan-Hui, Hsieh, Wan-Chen, Chiu, Tzu-Yuan, Liao, Jung-Chi, Chiu, Yen-Ling, Chen, Shih-Yu, Yu, Chong-Jen, Tsai, Hsing-Chen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/2; 13/21; 13/31; 14/19; 38/39; 49/91; 59/5; 631/250/1619/554/2509; 631/337/176; 631/67/580; 64/60; 692/4028/67/1612; 82/58; Actin; Actin Cytoskeleton - drug effects; Actin Cytoskeleton - metabolism; Adaptive systems; Adhesion; Animals; Cell activation; Cell adhesion molecules; Cell Line, Tumor; Chromatin; Clinical trials; Combinatorial analysis; Cytoskeleton; Cytoskeleton - drug effects; Cytoskeleton - metabolism; Cytotoxicity; Cytotoxicity, Immunologic - drug effects; Cytotoxicity, Immunologic - genetics; Decitabine - pharmacology; Deoxyribonucleic acid; Depletion; DNA; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methylation; DNA methyltransferase; Enzyme Inhibitors - pharmacology; Epigenesis, Genetic - drug effects; Epigenetics; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Immune system; Immunological Synapses - drug effects; Immunological Synapses - genetics; Immunotherapy; Inhibitors; Isotope Labeling; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lymphocyte Activation - drug effects; Lymphocyte Activation - genetics; Lymphocyte Subsets - drug effects; Lymphocyte Subsets - metabolism; Lymphocytes; Lymphocytes T; Lysis; Major histocompatibility complex; Male; Mice; Mice, Inbred NOD; multidisciplinary; Phosphotyrosine - metabolism; Proteomics; Receptors, Antigen, T-Cell, gamma-delta - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Solid tumors; Subgroups; Survival Analysis; Synapses; Toxicity; Tumor Suppressor Protein p53 - metabolism; Tumors; Up-Regulation - drug effects; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22433-4

γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an MHC-unrestricted manner. Trials of adoptive γδ T cell transfer in solid tumors have had limited success. Here, we show that DNA methyltransferase inhibitors (DNMTis) upregulate surface molecules on cancer cells related to γδ T cell activation using quantitative surface proteomics. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded Vδ1-enriched γδ T cells. Mechanistically, DNMTi enhances immune synapse formation and mediates cytoskeletal reorganization via coordinated alterations of DNA methylation and chromatin accessibility. Genetic depletion of adhesion molecules or pharmacological inhibition of actin polymerization abolishes the potentiating effect of DNMTi. Clinically, the DNMTi-associated cytoskeleton signature stratifies lung cancer patients prognostically. These results support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management. Gamma delta (γδ) T cells have potential for use in immunotherapy against tumours. Here, the authors demonstrate that treatment of tumours with DNA methyltransferase inhibitors modulates cytoskeleton arrangements, upregulates adhesion molecules and increases tumour killing by γδ T cells.