[en] 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 (BECN1) on the infiltration of NK cells into melanomas. We show that, in addition to inhibiting tumor growth, targeting BECN1 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 CCL5 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 BECN1, targeting other autophagy genes, such as ATG5, p62/SQSTM1, or inhibiting autophagy pharmacologically by chloroquine, also induced the expression of CCL5 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Mgrditchian, T; Laboratory of Experimental Cancer Research ; Luxembourg Institute of Health > Department of Oncology
Arakelian, T; Laboratory of Experimental Cancer Research, Luxembourg Institute of Health > Department of Oncology
Paggetti, J; Laboratory of Experimental Cancer Research, Luxembourg Institute of Health > Department of Oncology
Noman, MZ; Laboratory of Experimental Cancer Research, Luxembourg Institute of Health > Department of Oncology
Viry, E; Laboratory of Experimental Cancer Research, Luxembourg Institute of Health > Department of Oncology
Moussay, E; Laboratory of Experimental Cancer Research, Luxembourg Institute of Health > Department of Oncology
Van Moer, K; Laboratory of Experimental Cancer Research, Luxembourg Institute of Health > Department of Oncology
Kreis, Stephanie ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Guerin, C; National Cytometry Platform, Luxembourg Institute of Health > Department of Infection and Immunity
Buart, S; Gustave Roussy Cancer Center > INSERM UMR 1186
Robert, C; Gustave Roussy Cancer Center > INSERM UMR 981,
Borg, C; University Hospital of Besançon > Department of Medical Oncology
Vielh, P; Laboratoire National de Santé, Luxembourg
Chouaib, S; Gustave Roussy Cancer Center, > INSERM UMR 1186
Berchem, G; Centre Hospitalier du Luxembourg ; Laboratory of Experimental Cancer Research, > Department of Oncology
Janji, B; Laboratory of Experimental Cancer Research, Luxembourg Institute of Health, > Department of Oncology