TY - JOUR
T1 - Targeting autophagy inhibits melanoma growth by enhancing NK cells infiltration in a CCL5-dependent manner
AU - Mgrditchian, Takouhie
AU - Arakelian, Tsolere
AU - Paggetti, Jérôme
AU - Noman, Muhammad Zaeem
AU - Viry, Elodie
AU - Moussay, Etienne
AU - Van Moer, Kris
AU - Kreis, Stephanie
AU - Guerin, Coralie
AU - Buart, Stephanie
AU - Robert, Caroline
AU - Borg, Christophe
AU - Vielh, Philippe
AU - Chouaib, Salem
AU - Berchem, Guy
AU - Janji, Bassam
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Lea Guyonnet from the National Cytometry Platform at Luxembourg Institute of Health for her assistance in flow cytometry analysis; Olivia Bawa from the Gustave Roussy Cancer Center for her assistance in immunohistochemistry staining; and Cristina Maximo from Luxembourg Institute of Health for proofreading the manuscript. This work was supported by grants from Fond National de la Recherche, Luxembourg (Grant FNR-AFR 7842786 to T.M.), Luxembourg Institute of Health (Grant LHCE 2013 11 05 to B.J.), Fonds de la Recherche Scientifique FNRS Televie (Grants 7.6503.16 to T.A. and B.J., 7.4664.15 to M.Z.N. and B.J., and 7.4571.15 to E.V. and B.J.), Fondation Cancer, Luxembourg (Grants FC/2012/02 and F/2016/ 01 to B.J. and G.B.), Calouste Gulbenkian Foundation (Grant P.1333237 to T.M. and B.J.), Ligue Contre le Cancer (Équipes Labellisées), and Institut National du Cancer (to S.C.).
Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
PY - 2017/10/31
Y1 - 2017/10/31
N2 - 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 pharma-cologically 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.
AB - 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 pharma-cologically 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.
KW - Autophagy
KW - CCL5
KW - Immunotherapy
KW - Melanoma
KW - Natural killer
UR - http://www.scopus.com/inward/record.url?scp=85032677061&partnerID=8YFLogxK
U2 - 10.1073/pnas.1703921114
DO - 10.1073/pnas.1703921114
M3 - Article
C2 - 29078276
AN - SCOPUS:85032677061
SN - 0027-8424
VL - 114
SP - E9271-E9279
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 44
ER -