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
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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