Epigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T cell-mediated cytotoxicity in lung cancer
Autor: | Chi Liu, Chia-Chi Fan, Shu-Yung Lin, Xuan-Hui Lin, Rueyhung R Weng, Hsuan-Hsuan Lu, Yi-Chieh Wu, Tai-Chung Huang, Shih-Yu Chen, Tzu-Yuan Chiu, Yi-Hsiu Juan, Rong-Shan Lin, Hsing-Chen Tsai, Jung-Chi Liao, Chong-Jen Yu, Zheng-Ci Hung, Wan-Chen Hsieh, Yi-Jhen Huang, Yen-Ling Chiu, Chien-Ting Lin |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Cytotoxicity Immunologic Male Lung Neoplasms Immunological Synapses medicine.medical_treatment General Physics and Astronomy Lymphocyte Activation Immunological synapse Epigenesis Genetic 0302 clinical medicine Mice Inbred NOD DNA (Cytosine-5-)-Methyltransferases Enzyme Inhibitors Cytoskeleton Multidisciplinary Chemistry Receptors Antigen T-Cell gamma-delta Acquired immune system Up-Regulation Gene Expression Regulation Neoplastic Actin Cytoskeleton medicine.anatomical_structure 030220 oncology & carcinogenesis Isotope Labeling Tumour immunology Epigenetics Lung cancer Gammadelta T cells T cell Science Decitabine General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Immune system Antigen Cell Line Tumor medicine Animals Humans RNA Messenger Phosphotyrosine General Chemistry Immunotherapy Survival Analysis Xenograft Model Antitumor Assays Lymphocyte Subsets 030104 developmental biology Cancer cell Cancer research T cell mediated cytotoxicity Tumor Suppressor Protein p53 |
Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021) Nature Communications |
ISSN: | 2041-1723 |
Popis: | 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. |
Databáze: | OpenAIRE |
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