Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors
© 2019 Elsevier Inc. 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. Dangaj et al. show that tumor cell-expressed CCL5 and macrophage- and DC-expressed CXCL9 are important for the infiltration of T cells into tumors, a process that also requires recognition of tumor antigens by T cells. CCL5 is often epigenetically silenced in tumor cells but can be reactivated by Decitabine.
Dangaj, Denarda; Bruand, Marine; Grimm, Alizée J.; Ronet, Catherine; Barras, David; Duttagupta, Priyanka A.; Lanitis, Evripidis; Duraiswamy, Jaikumar; Tanyi, Janos L.; Benencia, Fabian; Conejo-Garcia, Jose; Ramay, Hena R.; Montone, Kathleen T.; Powell, Daniel J.; Gimotty, Phyllis A.; Facciabene, Andrea; Jackson, Donald G.; Weber, Jeffrey S.; Rodig, Scott J.; Hodi, Stephen F.; Kandalaft, Lana E.; Irving, Melita; Zhang, Lin; Foukas, Periklis; Rusakiewicz, Sylvie; Delorenzi, Mauro; and Coukos, George, "Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors" (2019). Biomedical Sciences Open Access Publications. 22.