title: Protective role of the inflammatory CCR2/CCL2 chemokine pathway through recruitment of type 1 cytotoxic γδ T lymphocytes to tumor beds.
abstract: Tumor-infiltrating lymphocytes (TILs) are important prognostic factors in cancer progression and key players in cancer immunotherapy. Although γδ T lymphocytes can target a diversity of tumor cell types, their clinical manipulation is hampered by our limited knowledge of the molecular cues that determine γδ T cell migration toward tumors in vivo. In this study we set out to identify the chemotactic signals that orchestrate tumor infiltration by γδ T cells. We have used the preclinical transplantable B16 melanoma model to profile chemokines in tumor lesions and assess their impact on γδ TIL recruitment in vivo. We show that the inflammatory chemokine CCL2 and its receptor CCR2 are necessary for the accumulation of γδ TILs in B16 lesions, where they produce IFN-γ and display potent cytotoxic functions. Moreover, CCL2 directed γδ T cell migration in vitro toward tumor extracts, which was abrogated by anti-CCL2 neutralizing Abs. Strikingly, the lack of γδ TILs in TCRδ-deficient but also in CCR2-deficient mice enhanced tumor growth in vivo, thus revealing an unanticipated protective role for CCR2/CCL2 through the recruitment of γδ T cells. Importantly, we demonstrate that human Vδ1 T cells, but not their Vδ2 counterparts, express CCR2 and migrate to CCL2, whose expression is strongly deregulated in multiple human tumors of diverse origin, such as lung, prostate, liver, or breast cancer. This work identifies a novel protective role for CCL2/CCR2 in the tumor microenvironment, while opening new perspectives for modulation of human Vδ1 T cells in cancer immunotherapy.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
authors.forename: Telma
authors.initials: T
authors.lastname: Lança
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Costa
authors.forename: Natacha
authors.initials: N
authors.lastname: Gonçalves-Sousa
authors.forename: Margarida
authors.initials: M
authors.lastname: Rei
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Grosso
authors.forename: Carmen
authors.initials: C
authors.lastname: Penido
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva-Santos
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D054390:Receptors, CCR2 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: C111835:CCL2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054390:Receptors, CCR2