Natural Killer (NK) cells play a crucial role in controlling tumors, and finding ways to increase their infiltration into tumors could improve NK-based immunotherapies. Researchers report that targeting the autophagy gene BECN1 in melanoma tumors inhibits tumor growth and increases the infiltration of functional NK cells into BECN1-defective tumors, compared with tumors with functional BECN1.

NK cell infiltration into the tumor bed was dependent on the transcriptional overexpression of the chemokine gene CCL5 because silencing CCL5 suppressed NK cell infiltration. Similar to BECN1, targeting other autophagy genes or pharmacologically inhibiting autophagy using chloroquine also induced the expression of CCL5 in melanoma cells.

The mechanism of CCL5 upregulation involved the enhanced phosphorylation of its transcription factor, c-Jun, through impaired phosphatase PP2A catalytic activity and a corresponding increase in JNK phosphorylation.

Clinically, the authors found a positive correlation between the expression of CCL5 and an NK cell marker in melanoma patients, as well as patient survival. According to the authors, targeting autophagy induces a decrease in melanoma tumor volume by enhancing the NK cell infiltration into the tumor bed.

Therefore, the authors suggest, inhibiting autophagy in tumor cells represents an innovative strategy to improve NK-based immunotherapy. 

http://www.pnas.org/content/early/2017/10/12/1703921114