1. Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors.
- Author
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Dangaj D, Bruand M, Grimm AJ, Ronet C, Barras D, Duttagupta PA, Lanitis E, Duraiswamy J, Tanyi JL, Benencia F, Conejo-Garcia J, Ramay HR, Montone KT, Powell DJ Jr, Gimotty PA, Facciabene A, Jackson DG, Weber JS, Rodig SJ, Hodi SF, Kandalaft LE, Irving M, Zhang L, Foukas P, Rusakiewicz S, Delorenzi M, and Coukos G
- Subjects
- Animals, Antineoplastic Agents, Immunological pharmacology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Chemokine CCL5 genetics, Chemokine CCL5 immunology, Chemokine CCL5 metabolism, Chemokine CXCL9 genetics, Chemokine CXCL9 immunology, Chemokine CXCL9 metabolism, Coculture Techniques, Cytokines genetics, Cytokines immunology, DNA Methylation, Dendritic Cells drug effects, Dendritic Cells immunology, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Humans, Immunotherapy methods, Interferon-gamma genetics, Interferon-gamma immunology, Interferon-gamma metabolism, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Macrophages drug effects, Macrophages immunology, Mice, Inbred C57BL, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, Ovarian Neoplasms therapy, Paracrine Communication, Receptors, CXCR3 genetics, Receptors, CXCR3 immunology, Receptors, CXCR3 metabolism, Signal Transduction, CD8-Positive T-Lymphocytes metabolism, Chemotaxis, Leukocyte drug effects, Cytokines metabolism, Dendritic Cells metabolism, Lymphocyte Activation drug effects, Lymphocytes, Tumor-Infiltrating metabolism, Macrophages metabolism, Ovarian Neoplasms metabolism
- Abstract
We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8
+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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