title: Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors.
abstract: Immunotherapies have shown considerable efficacy for the treatment of various cancers, but a multitude of patients remain unresponsive for various reasons, including poor homing of T cells into tumors. In this study, we investigated the roles of the leukotriene B4 receptor, BLT1, and CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, under endogenous as well as vaccine-induced antitumor immune response in a syngeneic murine model of B16 melanoma. Significant accelerations in tumor growth and reduced survival were observed in both BLT1(-/-) and CXCR3(-/-) mice as compared with wild-type (WT) mice. Analysis of tumor-infiltrating leukocytes revealed significant reduction of CD8(+) T cells in the tumors of BLT1(-/-) and CXCR3(-/-) mice as compared with WT tumors, despite their similar frequencies in the periphery. Adoptive transfer of WT but not BLT1(-/-) or CXCR3(-/-) CTLs significantly reduced tumor growth in Rag2(-/-) mice, a function attributed to reduced infiltration of knockout CTLs into tumors. Cotransfer experiments suggested that WT CTLs do not facilitate the infiltration of knockout CTLs to tumors. Anti-programmed cell death-1 (PD-1) treatment reduced the tumor growth rate in WT mice but not in BLT1(-/-), CXCR3(-/-), or BLT1(-/-)CXCR3(-/-) mice. The loss of efficacy correlated with failure of the knockout CTLs to infiltrate into tumors upon anti-PD-1 treatment, suggesting an obligate requirement for both BLT1 and CXCR3 in mediating anti-PD-1 based antitumor immune response. These results demonstrate a critical role for both BLT1 and CXCR3 in CTL migration to tumors and thus may be targeted to enhance efficacy of CTL-based immunotherapies.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202; Department of Microbiology and Immunology, University of Louisville Health Sciences, Louisville, KY 40202;
authors.forename: Zinal S
authors.identifier: 0000-0003-4508-5944
authors.initials: ZS
authors.lastname: Chheda
authors.affiliation: James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202; Division of Medical Oncology, Department of Medicine, University of Louisville Health Sciences, Louisville, KY 40202; and.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Sharma
authors.affiliation: James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202; Department of Microbiology and Immunology, University of Louisville Health Sciences, Louisville, KY 40202;
authors.forename: Venkatakrishna R
authors.identifier: 0000-0002-4206-7305
authors.initials: VR
authors.lastname: Jala
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139.
authors.forename: Andrew D
authors.identifier: 0000-0001-9679-7912
authors.initials: AD
authors.lastname: Luster
authors.affiliation: James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202; Department of Microbiology and Immunology, University of Louisville Health Sciences, Louisville, KY 40202; H0bodd01@louisville.edu.
authors.forename: Bodduluri
authors.initials: B
authors.lastname: Haribabu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002465:Cell Movement / Q000276:immunology*; D002634:Chemotaxis, Leukocyte; D005786:Gene Expression Regulation; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C515188:Cxcr3 protein, mouse; C503704:Ltb4r1 protein, mouse; D054367:Receptors, CXCR3; D018102:Receptors, Leukotriene B4