CXCL10 produced by DC1 plays a pivotal role in inducing long-lasting type-1 CTLs that mediate an effective anti-brain tumor immune response Free

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We have previously demonstrated that type-1 CTLs efficiently traffic to the central nervous system (CNS) tumor site, and mediate anti-tumor responses in a CXCL10-dependent manner. We have developed a novel protocol to generate mouse bone marrow (BM)-derived DCs capable of inducing type-1 CTLs, which express a type-1 chemokine receptor CXCR3 and IFN-γ at high levels. C57BL/6 mouse-derived BM cells were cultured in the presence of GM-CSF for 6 days, and then further matured with IL-4, IFN-γ and a TLR3 ligand, poly-ICLC for 24 hours. These DCs (DC1) exhibited phenotype of mature DCs, and produced high levels of IL-12p70, IL-15, and CXCL10. C57BL/6 mice received subcutaneous immunizations with DC1 loaded with synthetic peptides encoding mouse GL261 glioma-derived CTL epitopes. These mice mounted higher levels of antigen-specific type-1 CTLs compared to mice immunized with standard DCs. Furthermore, DC1 treatment of mice bearing CNS GL261 glioma resulted in prolonged survival, associated with enhanced tumor-infiltration and systemic persistence of antigen-specific CD8+ T cells. Systemic administration of anti-CXCL10 mAb abrogated induction of CTLs as well as the therapeutic response in glioma-bearing mice. Taken together, these findings point to significant roles of a type-1 chemokine CXCL10 in DC1-based cancer immunotherapy.