title: Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease.
abstract: Despite immunogenicity, melanoma-specific vaccines have demonstrated minimal clinical efficacy in patients with established disease but enhanced survival when administered in the adjuvant setting. Therefore, we hypothesized that organs bearing metastatic-like melanoma may differentially produce T-cell chemotactic proteins over the course of tumor development. Using an established model of metastatic-like melanoma in lungs, we assessed the production of specific cytokines and chemokines over a time course of tumor growth, and we correlated chemokine production with chemokine receptor-specific T-cell infiltration. We observed that the interferon (IFN)-inducible CXCR3-cognate chemokines (CXCL9 and CXCL10) were significantly increased in lungs bearing minimal metastatic lesions, but chemokine production was at or below basal levels in lungs with substantial disease. Chemokine production was correlated with infiltration of the organ compartment by adoptively transferred CD8(+) tumor antigen-specific T cells in a CXCR3- and host IFNγ-dependent manner. Adenosine signaling in the tumor microenvironment (TME) suppressed chemokine production and T-cell infiltration in the advanced metastatic lesions, and this suppression could be partially reversed by administration of the adenosine receptor antagonist aminophylline. Collectively, our data demonstrate that CXCR3-cognate ligand expression is required for efficient T-cell access of tumor-infiltrated lungs, and these ligands are expressed in a temporally restricted pattern that is governed, in part, by adenosine. Therefore, pharmacologic modulation of adenosine activity in the TME could impart therapeutic efficacy to immunogenic but clinically ineffective vaccine platforms.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Clancy-Thompson
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Perekslis
authors.affiliation: Department of Pathology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Walburga
authors.initials: W
authors.lastname: Croteau
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Alexander
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Tamer B
authors.initials: TB
authors.lastname: Chabanet
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Turk
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Department of Pathology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Yina H
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. david.w.mullins@dartmouth.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Mullins
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D054367:Receptors, CXCR3 / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden
chemical_list: D018925:Chemokines; D016207:Cytokines; D008024:Ligands; D054367:Receptors, CXCR3; D000241:Adenosine