Regulation of CTL trafficking into tumors and anti-tumor immunity by chemoattractant receptors BLT1 and CXCR3 (TUM7P.1015)

Abstract

Abstract A major hurdle limiting the success of tumor immunotherapies in the clinic is poor recruitment of CD8+ T cells (Cytotoxic T Lymphocytes-CTL) into tumors despite efficient CTL responses in the periphery. However, little is known about the mechanisms that regulate their infiltration into tumors. We investigated the role of leukotriene B4 receptor, BLT1 and CXCR3, the receptor for CXCL9 and CXCL10 in anti-tumor immunity using a syngeneic B16 melanoma mice model. Significant acceleration in tumor growth and reduced survival was observed in both BLT1-/- and CXCR3-/- mice as compared to WT mice. Tumor immune infiltration studies revealed significant reduction of CTLs in BLT1-/- and CXCR3-/- tumors as compared to WT tumors, their frequencies being similar in the periphery. Adoptive transfer of WT but not BLT1-/- or CXCR3-/- CTLs reduced tumor growth in Rag2-/- animals due to enhanced WT CTL infiltration to tumors. Furthermore, adoptive transfer of BLT1-/-, CXCR3-/- or BLT1-/-CXCR3-/- CTLs together with WT CTLs showed that initial migration of BLT1+/+ CTLs to tumors facilitates additional CTL recruitment in a CXCR3 dependent manner. An anti-PD-1 antibody based vaccine completely lost its efficacy in both BLT1-/- and CXCR3-/- mice suggesting a requirement for these receptors in generating sustained anti-tumor immune response. These results demonstrate a critical role for BLT1 and CXCR3 in CTL migration to tumors and thus can be targeted to elicit effective anti-tumor responses.