Tumor cells have the ability to establish a protective, surrounding microenvironment that prevents efficient infiltration by the body’s cytotoxic immune cells. Natural killer (NK) cells, which play a role in combating cancer cells, are often undetected in tumor biopsies, suggesting a deterrence in the NK cell ability to penetrate tumors. In a recent study, researchers led by a team from the Luxembourg Institute of Health discover that targeting the process of autophagy in cancer enhances NK cell infiltration.
The team finds that when the intracellular recycling process known as autophagy is blocked, tumor cells increase their production of cytokines, which attract NK cells. Inhibition of a key autophagy protein, Beclin-1, in melanoma cells has shown an inhibition of tumor growth, as well as increased infiltration of NK cells into the tumors. The mechanism behind this recruitment, the team finds, is due to an increased production of the cytokine CCL5. RNAi silencing of CCL5 results in loss of NK cell and the return of tumor growth, confirming this cytokine’s crucial role. In addition to Beclin, targeting other genes involved in autophagy, as well as chemical-induced repression of autophagy also induces the expression of CCL5.
Looking at patient tumor biopsies, the team finds a positive correlation between the presence of CCL5 and NK cell signature markers. Furthermore, a high expression of CCL5 correlates with a significant improvement in the survival of melanoma patients. In their study published in the journal, Proceedings of the National Academy of Sciences (PNAS), the study authors conclude that targeting tumor autophagy for NK cell infiltration may benefit as a novel approach in cancer immunotherapy.
"Our study provides a cutting edge advance in the field of cancer immunotherapy and could specifically pave the way for more effective NK cell-based immunotherapies,” said senior investigator Bassam Janji. “We now know how we can switch an immunosuppressive tumor environment to an immunosupportive one, enabling the action of NK cells.”