Targeting autophagy blocks melanoma growth by bringing natural killer cells to the tumor battlefield

ABSTRACT

Solid tumors are able to establish and sustain an immune suppressive microenvironment, which prevents the infiltration of cytotoxic effector immune cells into the tumor bed. We showed that genetic targeting of the macroautophagy/autophagy gene Becn1/Beclin1 in B16-F10 tumors inhibits their growth by inducing a massive infiltration of functional natural killer (NK) cells into the tumor bed. Such infiltration is primarily due to the ability of BECN1-defective tumor cells to overexpress and release CCL5 cytokine in the tumor microenvironment by a mechanism involving the activation of the MAPK8/JNK-JUN/c-Jun signaling pathway. Clinically, we reported a strong positive correlation between the expression of NK cell marker and CCL5 in human melanoma tumors and more importantly, a significant increased survival is found in melanoma patients expressing a high level of CCL5. Overall, these findings highlight the impact of targeting autophagy in breaking the immunosuppressive tumor microenvironment barrier, thus allowing the trafficking of cytotoxic NK cells into the tumor bed. This study underscore the importance of autophagy inhibition in tumors as a novel therapeutic strategy to fully exploit NK cells antitumor properties in clinical settings.

KEYWORDS:

• autophagy
• Beclin 1
• cancer immunotherapy
• CCL5 cytokine
• Immune infiltration
• immunotherapy
• melanoma
• natural killer cells

Acknowledgments

This work was supported by grants from FNRS Televie (7.6503.16; 7.4664.15; 7.4571.15, and 7.4535.16), Luxembourg Institute of Health (LHCE 2013 11 05), “Fondation Cancer”, Luxembourg (F/2016/01) and the Kriibskrank Kanner Foundation (2016 08 15).

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Additional information

Funding

This work was supported by FNRS Televie [grant number 7.6503.16; 7.4664.15; 7.4571.15, and 7.4535.16]; Luxembourg Institute of Health [grant number LHCE 2013 11 05]; Fondation Cancer Luxembourg [grant number F/2016/01] and the Kriibskrank Kanner Foundation [grant number 2016 08 15]