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