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

Abstract

Elevated numbers of regulatory T cells (Treg) in patient tumors are known to inhibit efficient antitumor 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. Ninety-nine percent of 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 IL3/anti-IL3 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. Cancer Res; 77(2); 291-302. ©2016 AACR.

Human mast cells and basophils—How are they similar how are they different?

“…This elegant study highlights for the first time a role of basophils as immune cells exerting cancer‐promoting functions within tumor draining LNs. In two experimental models, almost complete (≅99%) depletion of Tregs resulted in rejection of melanoma . The latter effect was attributed, at least in part, to infiltrating basophils that attract CD8 + T cells via the production of CCL3 and CCL4.…”

“…Basophils have long been marginalized in immunological studies and they were erroneously regarded as minor relatives of mast cells. Recent advances in analytical tools for basophils have highlighted the non‐redundant roles of basophils not only in allergic inflammation but also in autoimmune disorders, microbial infections, immunodeficiencies, and cancer . In murine models, there is convincing evidence of the heterogeneity of basophils expressing the TSLP receptor or the IL‐3 receptor .…”

“…Human mast cells and basophils were first described and named in 1878 and 1879, respectively, by Paul Ehrlich who discovered their property to be stained by specific dyes . Mast cells and basophils are important cells of the immune system with critical role in allergic and autoimmune disorders, microbial infections, cardiovascular diseases, immunodeficiencies, and cancer …”

Role of LFA-1 and ICAM-1 in Cancer

“…In addition, in this melanoma model, eosinophils normalized the tumor vasculature and reprogrammed tumorassociated macrophages into inflammatory M1 type [27]. Similarly to eosinophils, when basophilia was induced in these mice by treatment with interleukin-13, enhanced T-cell infiltration and tumor rejection was obtained, indicating a similar anti-tumor role for basophils [28]. Other studies attribute an antitumor role to eosinophils in colon cancer [29].…”

“…For instance, the presence of regulatory T cells, which are immunosuppressive, in the microenvironment of many solid tumors and the importance of LFA-1 in the function of these cells [52], suggests that targeting LFA-1 in these tumors would limit the function of regulatory T cells and improve the action of the immune system against the tumor [27] [28]. The acquired knowledge from targeting LFA-1 in the treatment of inflammatory diseases can be helpful here [53].…”