GSE183530
PD-1 restrains glycolysis for histone acetylation to suppress T-cell lymphoma
PDCD1, which encodes for the PD-1 immune checkpoint receptor, is a key tumor suppressor in T cells that is recurrently inactivated in human T cell non-Hodgkin lymphomas (T-NHLs)1-3. The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis2. Nevertheless, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Using tractable mouse models of human T-NHL, we demonstrate that PD-1 activity in pre-malignant cells prevents cellular transformation by inhibiting the induction of rate-limiting factors for glucose uptake and conversion upon oncogenic T cell signaling. Furthermore, PD-1 negatively regulates ATP-citrate lyase (ACLY), which generates extramitochondrial acetyl-CoA for histone acetylation. Consequently, inactivation of PD-1 enables oncogene-expressing T cells to switch to glycolysis to metabolically fuel overt malignancy and unleashes ACLY activity to promote de novo histone acetylation to increase chromatin accessibility of oncogenic AP-1 transcription factors. Multimodal molecular and functional analyses of primary human T-NHL samples confirmed enforced glucose metabolism, epigenetic reprogramming, and AP-1 activation upon PDCD1 loss in patients. Thus, our results identified PD-1 as a central metabolic gatekeeper of T cell transformation and lymphoma progression and established a mechanistic link between the PD-1 checkpoint receptor and glucose-dependent histone acetylation. Together, these data uncover novel putative genotype-specific vulnerabilities in T-NHL and present a starting point for the exploration of PD-1 dependent epigenetic reprogramming in T cell biology. Overall design: H3K27ac ChIPseq in T cells