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The therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell– and T-lymphocyte–dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11b+CD11c+Ly6ChighLy6G−MHCII+ dendritic cell–like antigen-presenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen–specific T cells within neoplastic lesions as induced by anthracyclines. In addition, we found that tumors treated with anthracyclines manifest increased expression levels of the chemokine Ccl2. Such a response is important as neoplasms growing in Ccl2−/− mice failed to accumulate dendritic cell–like APCs in response to chemotherapy. Moreover, cancers developing in mice lacking Ccl2 or its receptor (Ccr2) exhibited suboptimal therapeutic responses to anthracycline-based chemotherapy. Altogether, our results underscore the importance of the CCL2/CCR2 signaling axis for therapeutic anticancer immune responses as elicited by immunogenic chemotherapy. Cancer Res; 74(2); 436–45. ©2013 AACR.

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. Cancer Res; 71(14); 4809–20. ©2011 AACR.

Current cancer management aims to integrate molecular signatures into the design of personalized therapies. Recent advances in “omics” done on tumor specimens have led to the identification of factors that either recognize cancers of dismal prognosis or pinpoint “druggable” signaling pathways, which can be interrupted by targeted therapies. However, accumulating evidence underscores the biological and clinical significance of immune predictors in several compartments (blood, serum, tumor) in a variety of malignancies. An additional aspect that has been overlooked is the bidirectional, tumor-host interaction during therapeutic intervention, suggesting that dynamic molecular, biochemical, and metabolic signatures should be developed in the future. We review immune parameters of prognostic or predictive value during cancer therapy, and highlight existing “descriptive-prognostic” and “functional-therapeutic” molecular signatures, with the hindsight of designing appropriate compensatory therapies. Cancer Res; 70(23); 9538–43. ©2010 AACR.

STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3−/− cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell–dependent and T lymphocyte–mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3−/− cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3Y705F) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3−/− cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3−/− and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells. Cancer Res; 75(18); 3812–22. ©2015 AACR.