GSE135278
The transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8+ T cell fitness and functionality
Tissue-resident memory CD8+ T cells (Trm) share characteristics and core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic and epigenetic regulation of Trm cell and TIL differentiation, maintenance and function are largely undefined. Furthermore, it is unknown whether metabolic and epigenetic manipulations can be employed to promote Trm/TIL functional programs for cancer immunotherapy. Here we report a critical mechanism programming the mitochondrial and epigenetic regulation of Trm/TIL functionality in situ. We found that mouse and human Trm/TIL expressed the transcription factor BHLHE40 and the BHLHE40-associated gene signature. Bhlhe40 was specifically required for Trm and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TILs reinvigoration following anti-PD therapy. Mechanistically, Bhlhe40 sustained Trm/TIL mitochondrial fitness for the promotion of a functional epigenetic state. Building on these findings, we also identified an epigenetic and metabolic regimen that promoted Trm/TIL gene signatures associated with tissue residency and poly-functionality through in vitro T cell screening. Strikingly, this regimen empowered the anti-tumor activity of CD8+ T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights on the local regulation of Trm and TIL function, and offer a viable strategy for developing novel immunotherapeutic means for cancer. Overall design: Examination of RNA expression in: in vitro activated CD8+ T cell from WT or Bhlhe40 deficient mice; TIL cells and Splenic CD8+ T cells from B16-OVA bearing WT mice; Trm cells from IAV infected WT or Bhlhe40 deficient mice and Splenic CD8+ T cells from IAV infected WT mice.