NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer

Abstract

Summary Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-κB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.

Codon bias confers stability to humanmRNAs

“…determinant of mRNA stability in human cells [28]. c-Rel, a protein encoded by the REL gene and a canonical nuclear factor jB (NF-jB) subunit, is expressed abundantly in differentiated lymphoid cells and has been shown to be vital in thymic regulatory T-cell development in addition to controlling cancer via activated regulatory T cells [74,75]. Indeed, the codon designations of optimal and nonoptimal codons also showed modest delineation of codons into GC3 and AT3 codons, respectively.…”

Treg programming and therapeutic reprogramming in cancer

“…A defining feature of TI‐Tregs is their highly activated phenotype . Treg activation within the TME leads to the induction of a repertoire of suppressive molecules, such as C TLA‐4, GITR, PD‐1 and LAG‐3 , which control antitumour immune responses.…”

“…CD28 engagement activates several cytosolic signalling pathways, but activation of lymphocyte cell‐specific protein tyrosine kinase (LCK) seems to be particularly important for Tregs . LCK is central to the activation and nuclear localization of the transcription factor nuclear factor of kappa light polypeptide gene enhancer in B‐cells (NF‐ κ B), which, as will be discussed later, is essential for the maintenance of the immunosuppressive activity of Tregs in cancers . Interestingly, the phosphatidylinositol 3‐kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway, which is also activated in response to CD28, has not proven to be important in establishing and maintaining the immunosuppressive Treg state.…”

“…Activated upon TCR/CD28 stimulation, the NF‐kB subunits p65 and c‐Rel are required for the development of Tregs in the thymus. However, only disruption of c‐Rel, either genetically or pharmacologically, reprogrammes TI‐Tregs to enhance cancer immunity . c‐Rel‐deficient TI‐Tregs exhibit reduced expression of genes associated with Treg activation – Itgae , Tigit , Klrg1 , Il1r2 , as well as downregulation of Foxp3, CD25 and Helios but, more importantly, these Tregs reprogramme into Th1‐like cells, expressing Eomes , Tbx21 , Il2 and Ifng …”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…Consistently in mice, the canonical NF-kB pathway of IKKβ and p65 and c-Rel NF-kB has been demonstrated to regulate CD4 T-cell functions and Treg development. [89][90][91] Tnfr deletion-rescued p65 À/À mice develop severe infections, leading to failure to thrive. [92,93] Furthermore, Hassall's corpuscles, which are differentiated from mTECs due to a lack of AIRE expression, [94] were observed in the medulla of human SCID patients, and a scant lymphoid population was seen in the thymus but was largely located in the medulla, [69] indicating that IKKβ mutations impair AIRE expression and mTEC development in SCID patients.…”