RNA polymerase II pausing factor NELF in CD8+ T cells promotes antitumor immunity
Bogang Wu, Xiaowen Zhang, Huai-Chin Chiang, Haihui Pan, Bin Yuan, Payal Mitra, Leilei Qi, Hayk Simonyan, Colin N. Young, Éric Yvon, Yanfen Hu, Nu Zhang, Rong Li
Abstract
T cell functions. How TCF1 partners with other transcription factors to regulate transcription remains unclear. Here we show that negative elongation factor (NELF), an RNA polymerase II (Pol II) pausing factor, cooperates with TCF1 in T cell responses to cancer. Deletion of mouse Nelfb, which encodes the NELFB subunit, in mature T lymphocytes impairs immune responses to both primary tumor challenge and tumor antigen-mediated vaccination. Nelfb deletion causes more exhausted and reduced memory T cell populations, whereas its ectopic expression boosts antitumor immunity and efficacy of chimeric antigen receptor T-cell immunotherapy. Mechanistically, NELF is associated with TCF1 and recruited preferentially to the enhancers and promoters of TCF1 target genes. Nelfb ablation reduces Pol II pausing and chromatin accessibility at these TCF1-associated loci. Our findings thus suggest an important and rate-limiting function of NELF in anti-tumor immunity.