Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors [TUMOR IMMUNOLOGY]

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.

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