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, Eric Yvon, Yanfen Hu, Nu Zhang and Rong Li ()
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Bogang Wu: The George Washington University
Xiaowen Zhang: The George Washington University
Huai-Chin Chiang: The George Washington University
Haihui Pan: The George Washington University
Bin Yuan: The George Washington University
Payal Mitra: The George Washington University
Leilei Qi: The George Washington University
Hayk Simonyan: The George Washington University
Colin N. Young: The George Washington University
Eric Yvon: The George Washington University Cancer Center School of Medicine & Health Sciences, The George Washington University
Yanfen Hu: The George Washington University
Nu Zhang: University of Texas Health San Antonio
Rong Li: The George Washington University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29869-2

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