Basophils Promote Tumor Rejection via Chemotaxis and Infiltration of CD8+ T Cells

Abstract

Elevated numbers of regulatory T-cells (Tregs) in patient tumors are known to inhibit efficient anti-tumor T-cell responses. To study the mechanisms controlling tumor rejection, we assessed different mouse models for Treg depletion. In Foxp3DTR knock-in mice, about 99% Treg depletion was achieved, resulting in complete rejection of transplanted HCmel12 melanomas in a CD8+ T cell-dependent way. In contrast, about 90% Treg depletion obtained in BAC transgenic Foxp3.LuciDTR4 mice failed to induce complete rejection of HCmel12 melanomas, demonstrating that residual Tregs were able to control CD8+ T cell responses against the tumor. 99% Treg depletion provoked drastic changes in the tumor microenvironment, such as strong infiltration of CD8+ T cells and basophils. Intratumoral basophils enhanced CD8+ T cell infiltration via production of chemokines CCL3 and CCL4; antibody-based blocking of these chemokines inhibited CD8+ T cell infiltration. Therapeutic induction of basophilia by IL-3/anti-IL-3 antibody complexes, combined with transfer of CD8 T-cells, resulted in enhanced T-cell infiltration and tumor rejection. Our study identifies a critical role basophils play in tumor rejection, and that this role can be exploited for therapeutic intervention.