Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

Abstract

Abundant macrophage infiltration of solid cancers commonly correlates with poor prognosis. Tumor-promoting functions of macrophages include angiogenesis, metastasis formation and suppression of Th1-type immune responses. We here show, that successful treatment of cervical carcinoma by synthetic long peptide (SLP) vaccines induced influx of cytokine producing CD8 T-cells that strongly altered the numbers and phenotype of intratumoral macrophages. Based on the expression of CD11b, CD11c, F4/80, Ly6C, Ly6G and MHC II we identified four myeloid subpopulations that increased in numbers from 2.0- to 8.7-fold in regressing tumors. These changes of the intratumoral myeloid composition coincided with macrophage recruitment by chemokines, including CCL2 and CCL5, and completely depended on a vaccine-induced influx of tumor-specific CD8 T-cell. CD4 T-cells were dispensable. Incubation of tumor cells with T-cell derived IFNγ and TNFα recapitulated the chemokine profile observed in vivo, confirming the capacity of anti-tumor CD8 T-cells to mediate macrophage infiltration of tumors. Strikingly, complete regressions of large established tumors depended on the tumor infiltrating macrophages that were induced by this immunotherapy, since a small drug inhibitor targeting CSF-1R diminished the number of intratumoral macrophages and abrogated the complete remissions. Survival rates after therapeutic SLP vaccination deteriorated in the presence of CSF-1R blockers. Together, these data show that therapeutic peptide vaccination induced cytokine producing T-cells that possess strong macrophage skewing capacity, required for tumor shrinkage. This warrants development of macrophage-polarizing rather than macrophage depleting agents.