HSF1 excludes CD8+ T cells from breast tumors via suppression of CCL5

Abstract

Heat shock factor 1 (HSF1) is a stress-responsive transcription factor known to promote malignancy of several cancers, including breast cancer. To study the relationship of HSF1 activity to breast cancer phenotypes, we generated a 23-gene HSF1 Activity Signature (HAS) that accurately reports HSF1 transcriptional activity. This signature accurately reported previously known functions of HSF1, including response to heat stress, as well as HSF1 relationship to breast cancer. Namely, the HAS reported increased activity in tumors compared to normal and association with worse patient outcomes. This HAS gene set was used to assess the association of HSF1 activity with immune cell types in breast cancer. Interestingly, the HAS was negatively associated with the presence of CD8+ T cells in breast tumors, which was also observed in primary patient tumor specimens. Depletion of HSF1 in the immune-competent 4T1-Balb/c model led to decreased tumor volume, which was rescued with depletion of CD8+ T cells, suggesting HSF1 suppresses CD8+ T cells to prevent immune-mediated killing of breast cancer cells. Furthermore, loss of HSF1 also caused increased expression and secretion of the chemokine CCL5, a known recruiter of CD8+ T cells. Depletion of CCL5 prevented the attraction of CD8+ T cells observed with loss of HSF1. These data demonstrate a model whereby HSF1 suppresses CCL5, leading to less CD8+ T cells in breast tumors preventing immune-mediated destruction. This novel mechanism may contribute to the low levels of antitumor immune cells frequently observed in breast cancer and may also suggest inhibition of HSF1 as a therapeutic strategy to increase immune infiltration into breast tumors.