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

Abstract Heat shock factor 1 (HSF1) is a stress-responsive transcription factor that promotes cancer cell malignancy. A novel HSF1 Activity Signature (HAS) was found to be negatively associated with antitumor immune cells in breast tumors. Knockdown of HSF1 decreased tumor size and caused an influx of several antitumor immune cells, most notably CD8+ T cells. Depletion of CD8+ T cells prevented tumors from shrinking after knockdown of HSF1, suggesting HSF1 prevents CD8+ T cell influx to avoid immune-mediated tumor killing. HSF1 was also found to suppress expression of CCL5, a chemokine for CD8+ T cells, that significantly contributed to the attraction of CD8+ T cells upon the loss of HSF1. This study demonstrates a model whereby HSF1 suppresses CCL5 leading to reduced CD8+ T cells in breast tumors that prevented immune-mediated destruction. For the first time, these studies indicate HSF1 suppresses antitumor immune activity within tumors.