RNA Polymerase II Pausing Factor NELF in CD8+ T Cells Promotes Anti-Tumor Immunity

The master transcriptional regulator T cell factor 1 (TCF1) is required for the anti-tumor functions of memory and stem-like CD8+ T cells. However, how TCF1 partners with other transcription factors to orchestrate the gene activation program critical for anti-tumor immunity remains poorly understood. Here we show that negative elongation factor B (NELFB), an RNA polymerase II pausing factor, cooperates with TCF1 in T cell responses to cancer. Genetic ablation of mouse Nelfb in mature T lymphocytes severely impaired anti-tumor immunity responding to both primary tumor challenge and tumor antigen-mediated vaccination. NELFB depletion resulted in more exhausted, and reduced memory, T cell populations, whereas its ectopic expression boosted host anti-tumor immunity and efficacy of chimeric antigen receptor (CAR) T-cell immunotherapy. Mechanistically, NELFB is physically associated with TCF1 and recruited preferentially to TCF1-enriched transcriptional enhancers and promoters in CD8+ T cells. Nelfb ablation significantly restricted chromatin accessibility to these TCF1-associated loci. Thus, NELFB is a previously unrecognized functional partner of TCF1 that potentiates the chromatin openness of TCF1-targeting regulatory elements. Our findings also suggest that augmenting NELFB expression in CD8+ T cells may improve therapeutic outcomes of anti-cancer CAR-T immunotherapies. CD8+ T cells were isolated from WT/KO mice spleen for scRNA-seq, ATAC-seq, Pol II ChIP-seq, bulk RNA-seq. WT CD8+ T cells from WT mice spleen were used for NELFB ChIP-seq.