Fiche publication
Date publication
juin 2024
Journal
Cancer letters
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BOIDOT Romain
,
Dr VEGRAN Frédérique
Tous les auteurs :
Vidana Gamage HE, Albright ST, Smith AJ, Farmer R, Shahoei SH, Wang Y, Fink EC, Jacquin E, Weisser E, Bautista RO, Henn MA, Schane CP, Nelczyk AT, Ma L, Gupta AD, Bendre SV, Nguyen T, Tiwari S, Krawczynska N, He S, Tjoanda E, Chen H, Sverdlov M, Gann PH, Boidot R, Vegran F, Fanning SW, Apet L, Hergenrother PJ, Nelson ER
Lien Pubmed
Résumé
Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (T). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of T. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of T expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.
Mots clés
DSHN-OMe, Small heterodimer partner, Treg, cholesterol, nuclear receptor
Référence
Cancer Lett. 2024 06 27;:217086
