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

Abstract

Cells have evolved mechanisms for response to external stressors in order to maintain cell viability in the face of changes in the environment. The response to heat stress is driven by the transcription factor heat shock factor 1 (HSF1), which is considered the master regulator of the heat shock response. Here we report a new HSF1 gene signatured termed “HSF1 Activity Signature,” or HAS, which is a 23-gene signature that more specifically assesses HSF1 transcriptional activity. We first identified genes that are direct transcriptional targets of HSF1 utilizing more than 40 ChIP-Seq samples in the public domain. Genes identified from ChIP-Seq were then reduced by removing genes whose expression was not altered or showed increased expression with the knockdown of HSF1. These genes were then assessed for their correlation with every other gene across 11 cancer expression datasets to develop an adjacency matrix to identify subgroups of genes that have high inter-gene correlation. The resulting 23-gene set (HAS) was then tested for its performance of assessing HSF1 activity wherein it was found to decreased when HSF1 was knocked down and increase in response to heat shock. The HAS was also able to predict outcomes of breast cancer patients that are previously observed such as high HAS was associated with worse overall survival and metastasis-free survival. This association with cancer patient outcomes extended to many other tumor types. In total, the 23-gene set we termed HAS, is an accurate tool to assess HSF1 activity from transcript expression data that is not limited to cancer-related functions of HSF1.