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.
Highlights
Chemotherapy treatment in cancer has long been associated with development of systemic immunosuppression [1, 2]
We show that CD8 T cells and IFN-g are critical effectors of IL-1b- and IL-17– dependent signaling in response to doxorubicin-treated breast tumors and sarcomas, and corroborating this, we report that CD8a, CD8b, and IFN-g gene expression levels in breast cancer patients treated with anthracycline chemotherapy correlate with treatment response
Adaptive immunity and IFN-g have been implicated in the immunogenic effects of chemotherapy [10, 32], but CD8þ T cells have not been previously directly shown to contribute to the antitumor activity of doxorubicin
Summary
Chemotherapy treatment in cancer has long been associated with development of systemic immunosuppression [1, 2]. The immunostimulatory properties of chemotherapy have been associated with increased expression of "stress-like" molecules by damaged or dying tumor cells, such as killer cell lectin-like receptor sub-family K ligands, Fas, and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) death receptors and HSPs, that render cells receptive to direct attack by cells of the innate immune system; including natural killer (NK) cells, natural killer T cells (NKT cells), and gd T cells Certain alarmins or danger-associated molecular patterns are expressed or released during tumor cell death induced by immunogenic chemotherapeutic agents, including anthracyclines. These include translocation of the endoplasmic reticulum resident calreticulin complex to the plasma membrane, providing an "eat-me" signal [5,6,7] and release of the nuclear alarmin HMGB1 to engage TLR-4 on dendritic cells Anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx À or Nlrp3À or Casp1deficient hosts [10]
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