The NK cell stress response status modulates anti-tumor immunity [ChIPmentation]

The tumor microenvironment (TME) comprises numerous forms of cellular stress, which can activate Heat Shock Factor 1 (HSF1), the master transcription factor of the proteotoxic stress response. We profiled HSF1 activity across tumor-infiltrating immune populations, revealing the highest activity in CD8+ T cells and the lowest in natural killer (NK) cells. To elucidate the mechanisms through which HSF1 regulates immune surveillance, we generated an in vivo model of augmented HSF1 activity. Tumor challenge revealed that accumulation of HSF1 dampens NK-mediated tumor immunity and impairs both cytotoxicity and production of interferon gamma (IFN-γ) in NK cells. Single-cell transcriptional profiling identified a loss of anti-tumor signaling pathways, including interferon signaling, within the HSF1-enhanced TME. In NK cells, integration of chromatin accessibility with transcriptomics revealed that HSF1 deregulates accessibility and expression of genes encoding for NK receptors, leading to an inhibitory bias. HSF1 ChIPmentation was performed on primary NK cells extracted from 5 WT or 5 HSF1-S303/7A animals. Naïve NK cells were used immediately after isolation.