RNA polymerase II pausing factor NELF in CD8+ T cells promotes antitumor immunity

• Published in: Nature communications 2022-04, Vol.13 (1), p.2155-2155, Article 2155
• Main Authors: Wu, Bogang, Zhang, Xiaowen, Chiang, Huai-Chin, Pan, Haihui, Yuan, Bin, Mitra, Payal, Qi, Leilei, Simonyan, Hayk, Young, Colin N., Yvon, Eric, Hu, Yanfen, Zhang, Nu, Li, Rong
• Format: Article
• Language: English
• Subjects: 13; 13/31; 14; 38; 38/15; 38/23; 38/39; 38/91; 42; 45; 631/250/1619/554; 631/250/251; 631/337/572; 631/67/580; 64; 64/60; Ablation; Animals; Anticancer properties; Antigens; Antitumor activity; CD8 antigen; CD8-Positive T-Lymphocytes; Chimeric antigen receptors; Chromatin; Clonal deletion; Deletion; DNA-directed RNA polymerase; Ectopic expression; Elongation; Enhancers; Hepatocyte nuclear factor 1; Humanities and Social Sciences; Immunity; Immunological memory; Immunotherapy; Lymphocytes; Lymphocytes T; Memory cells; Mice; multidisciplinary; Promoter Regions, Genetic; Ribonucleic acid; RNA; RNA polymerase; RNA polymerase II; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Science; Science (multidisciplinary); Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; Vaccination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29869-2

T cell factor 1 (TCF1) is required for memory and stem-like CD8 + 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. Negative elongation factor B (NELFB) is one of the four subunits of the NELF complex that controls RNA polymerase II pausing. Here the authors show that, by associating with the key T cell transcription factor TCF1, NELFB is required for eliciting CD8 + T cell memory and anti-tumor immune responses.