Distinct regulation of CD4+ T-cell function in cancer and autoimmunity by canonical NF-kappaB subunits.

Abstract Whereas CD4+ effector T cells (Teff cells) are critical to limit tumor progression, uncontrolled Teff cell activation can also lead autoimmunity; however the molecular basis of these functions elusive. Here we investigated selective distinct NF-kappaB transcription factors in function cells. Using mice carrying conditional ablation canonical NF-kB subunits RelA and c-Rel, cells, found that RelA, rather than shaped transcriptome steady-state their ability polarize toward TH17 lineage, by directly binding genes encoding cytokines other factors. Similar conclusions could be reached using CRISPR/Cas9-edited primary human Consistently, – but not c-Rel-deficient were fully protected against neuro-inflammation a murine model multiple sclerosis. Mechanistically, priming situ reactivation, impaired RelA-deficient mice. Next, roles cancer immunity. Strikingly, Teff-restricted accumulation microenvironment melanoma, resulting enhanced burden. In addition, c-Rel-deficiency abrogated therapeutic effect PD-1-blockade. Accordingly, melanoma patients, expression c-Rel-dependent was associated with prolonged survival better response immunotherapy. Together, our data highlight novel, context-dependent, regulators function. We propose division labor between different pathway, paving way subunit-targeted immunotherapies autoimmunity cancer.