We established a positive correlation between a fibrotic phenotype in human breast tumors — especially the Her2 and basal-like breast cancer subtypes — and CD45 and CD68 positive immune cell infiltration. We were interested in elucidating how this fibrotic phenotype may influence the immune response. To address this question, we examined if matrix stiffness alters the function of STAT3, a central regulator of tumor inflammation. We hypothesize that tissue fibrosis promotes STAT3 signaling in mammary tumor cells and alter the cytokine milieu to induce a pro-tumor immune response. We found that ECM stiffness directly enhanced STAT3 phosphorylation in tumor cells both in vitro and in vivo. Our data suggest the fibrotic phenotype promotes STAT3 activity, enhancement of which may drive a pro-tumor immune response. Indeed, we observed several alterations in cytokines and immune cell populations upon STAT3 ablation consistent with anti-tumor immune response. Interestingly, our data also suggest STAT3 knockout in tumor cells doesn't necessary influence immune cell infiltration, but rather their differentiation in mammary tumors. Finally, we investigated if matrix stiffness has potentiated macrophage differentiation when cultured with specific immunosuppressive cytokines. Overall, our work reveals a novel mechanistic insight into how a pro-tumor immune response stems from the interplay between fibrosis and STAT3 signaling in tumor cells. As such, our findings may stimulate an interest in exploring combinational treatment options with anti-fibrotic agents and immunotherapy.
Citation Format: Ori Maller, Luke Cassereau, Allison Drain, Brian Ruffell, Irene Acerbi, Miranda Broz, Jennifer Munson, Melody Swartz, Matthew Krummel, Lisa Coussens, Valerie Weaver. A role for fibrosis in promoting pro-tumor immune response in breast cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A098.
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