title: Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors.
abstract: We show, in a series of established experimental breast adenocarcinomas and fibrosarcomas induced by carcinogen de novo in mice, that the therapeutic efficacy of doxorubicin treatment is dependent on CD8 T cells and IFN-γ production. Doxorubicin treatment enhances tumor antigen-specific proliferation of CD8 T cells in tumor-draining lymph nodes and promotes tumor infiltration of activated, IFN-γ-producing CD8 T cells. Optimal doxorubicin treatment outcome also requires both interleukin (IL)-1β and IL-17 cytokines, as blockade of IL-1β/IL-1R or IL-17A/IL-17Rα signaling abrogated the therapeutic effect. IL-23p19 had no observed role. The presence of γδ T cells, but not Jα18(+) natural killer T cells, at the time of doxorubicin treatment was also important. In tumor samples taken from breast cancer patients prior to treatment with anthracycline chemotherapy, a correlation between CD8α, CD8β, and IFN-γ gene expression levels and clinical response was observed, supporting their role in the therapeutic efficacy of anthracyclines in humans. Overall, these data strongly support the pivotal contribution of both innate and adaptive immunity in treatment outcomes of anthracycline chemotherapy.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Mattarollo
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.forename: Helene
authors.initials: H
authors.lastname: Duret
authors.forename: Yuting
authors.initials: Y
authors.lastname: Ma
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000276:immunology / Q000494:pharmacology*; D016827:CD8 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004317:Doxorubicin / Q000276:immunology / Q000494:pharmacology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000903:Antibiotics, Antineoplastic; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C477867:CD8beta antigen; D018984:Epitopes, T-Lymphocyte; D020381:Interleukin-17; D004317:Doxorubicin; D007371:Interferon-gamma