Targeting autophagy inhibits melanoma growth by enhancing NK cells infiltration in a CCL5-dependent manner.
Fiche publication
Date publication
octobre 2017
Journal
Proceedings of the National Academy of Sciences of the United States of America
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BORG Christophe
Tous les auteurs :
Mgrditchian T, Arakelian T, Paggetti J, Noman MZ, Viry E, Moussay E, Van Moer K, Kreis S, Guerin C, Buart S, Robert C, Borg C, Vielh P, Chouaib S, Berchem G, Janji B
Lien Pubmed
Résumé
While blocking tumor growth by targeting autophagy is well established, its role on the infiltration of natural killer (NK) cells into tumors remains unknown. Here, we investigate the impact of targeting autophagy gene Beclin1 () on the infiltration of NK cells into melanomas. We show that, in addition to inhibiting tumor growth, targeting increased the infiltration of functional NK cells into melanoma tumors. We provide evidence that driving NK cells to the tumor bed relied on the ability of autophagy-defective tumors to transcriptionally overexpress the chemokine gene Such infiltration and tumor regression were abrogated by silencing CCL5 in BECN1-defective tumors. Mechanistically, we show that the up-regulated expression of CCL5 occurred through the activation of its transcription factor c-Jun by a mechanism involving the impairment of phosphatase PP2A catalytic activity and the subsequent activation of JNK. Similar to , targeting other autophagy genes, such as , /, or inhibiting autophagy pharmacologically by chloroquine, also induced the expression of in melanoma cells. Clinically, a positive correlation between CCL5 and NK cell marker NKp46 expression was found in melanoma patients, and a high expression level of CCL5 was correlated with a significant improvement of melanoma patients' survival. We believe that this study highlights the impact of targeting autophagy on the tumor infiltration by NK cells and its benefit as a novel therapeutic approach to improve NK-based immunotherapy.
Mots clés
CCL5, autophagy, immunotherapy, melanoma, natural killer
Référence
Proc. Natl. Acad. Sci. U.S.A.. 2017 Oct 31;114(44):E9271-E9279