title: 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.
authors.affiliation: Division of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Sektioglu
authors.affiliation: Division of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Rafael
authors.initials: R
authors.lastname: Carretero
authors.affiliation: Division of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Bulbuc
authors.affiliation: Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bald
authors.affiliation: Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.affiliation: Immunology Program, Howard Hughes Medical Institute and Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.affiliation: Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. hammerling@dkfz.de.
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001491:Basophils / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D008212:Lymphocyte Depletion / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D019139:Tumor Escape / Q000276:immunology