University of California, San Francisco San Francisco United States
We previously 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 are currently 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 subsequently alters 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. 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.