| Literature DB >> 31185212 |
Denarda Dangaj1, Marine Bruand1, Alizée J Grimm1, Catherine Ronet1, David Barras2, Priyanka A Duttagupta3, Evripidis Lanitis1, Jaikumar Duraiswamy4, Janos L Tanyi5, Fabian Benencia6, Jose Conejo-Garcia7, Hena R Ramay8, Kathleen T Montone9, Daniel J Powell5, Phyllis A Gimotty10, Andrea Facciabene5, Donald G Jackson11, Jeffrey S Weber12, Scott J Rodig13, Stephen F Hodi14, Lana E Kandalaft1, Melita Irving1, Lin Zhang5, Periklis Foukas15, Sylvie Rusakiewicz1, Mauro Delorenzi2, George Coukos16.
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.Entities:
Keywords: CCL5; CXCL10; CXCL9; IFN-γ; T cell trafficking in the tumor; TILs (tumor-infiltrating lymphocytes); checkpoint blockade; epigenetic silencing; immunoreactive tumors; inducible and constitutive chemokines
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Year: 2019 PMID： 31185212 PMCID： PMC6961655 DOI： 10.1016/j.ccell.2019.05.004
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743