The IRENA lncRNA converts chemotherapy-polarized tumor-suppressing macrophages to tumor-promoting phenotypes in breast cancer
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence un mécanisme par lequel le long ARN non codant de l'activateur (sensible à l'interféron) du facteur nucléaire kappaB favorise la conversion des macrophages suppresseurs de tumeurs en macrophages protumoraux après une chimiothérapie
Although chemotherapy can stimulate antitumor immunity by inducing interferon (IFN) response, the functional role of tumor-associated macrophages in this scenario remains unclear. Here, we found that IFN-activated proinflammatory macrophages after neoadjuvant chemotherapy enhanced antitumor immunity but promoted cancer chemoresistance. Mechanistically, IFN induced expression of cytoplasmic long noncoding RNA IFN-responsive nuclear factor-κB activator (IRENA) in macrophages, which triggered nuclear factor-κB signaling via dimerizing protein kinase R and subsequently increased production of protumor inflammatory cytokines. By constructing macrophage-conditional IRENA-knockout mice, we found that targeting IRENA in IFN-activated macrophages abrogated their protumor effects, while retaining their capacity to enhance antitumor immunity. Clinically, IRENA expression in post-chemotherapy macrophages was associated with poor patient survival. These findings indicate that lncRNA can determine the dichotomy of inflammatory cells on cancer progression and antitumor immunity and suggest that targeting IRENA is an effective therapeutic strategy to reversing tumor-promoting inflammation.
Nature Cancer 2021