Targeting autophagy inhibits melanoma growth by enhancing NK cells infiltration in a CCL5-dependent manner

While blocking tumor growth by targeting autophagyis well established, its role on the infiltration of natural killer (NK) cells into tumors remains unknown. Here, we investigate the impact of targeting autophagygene Beclin1 ( BECN1) on the infiltration of NK cells into melanomas. We show that, in addition to inhibiting tumor growth, targeting BECN1increased 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 CCL5in BECN1-defective tumors. Mechanistically, we show that the up-regulated expression of CCL5occurred 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 autophagygenes, such as ATG5, p62 / SQSTM1 , or inhibiting autophagypharmacologically by chloroquine, also induced the expression of CCL5in melanoma cells. Clinically, a positive correlation between CCL5and NK cell marker NKp46 expression was found in melanoma patients, and a high expression level of CCL5was correlated with a significant improvement of melanoma patients’ survival. We believe that this study highlights the impact of targeting autophagyon the tumor infiltration by NK cells and its benefit as a novel therapeutic approach to improve NK-based immunotherapy.