Combining selective pharmacological inhibitors of autophagy with NK immune checkpoint blockade anti-KIR: An innovative approach to improve NK-based cancer immunotherapy

Given their ability to kill tumor cells without prior sensitization, NK cells are powerful tool to be exploited in cancer immunotherapy. However, NK-based cancer immunotherapy were often disappointing and failed in many protocols in clinic. To overcome this failure, extensive efforts over the last two decades using NKs in the treatment of human cancers were mainly focused on strategies aiming to reactivate their cytotoxicity. Similar to T-cell immune checkpoint blockade (PD-1/PD-L1 and CTLA4), these strategies relied on the development antibodies targeting NK-cell immune checkpoint blockades, such asanti-KIR blocking antibodies. We believe that the modest success of these strategies to drive strong and sustained NK-mediated immune response could be attributed to the fact that tumors remained infrequently infiltrated by NK cells. Several lines of evidence suggest that tumor derived factors contribute to the establishment of so called immune-suppressive or immune-desert tumor microenvironment which prevents the infiltration of cytotoxic immune cells, including NK. Therefore, strategies able to switch the immune-suppressive tumor landscape to an immune supportive one would significantly improve NK-based cancer immunotherapies. We have previously reported that targeting autophagy in tumor cells induced a massive infiltration of NKs into melanoma through the expression of the cytokine CCL5. The present project aims to evaluate the therapeutic benefit of combining selective pharmacological inhibitors of autophagy (Vps34 inhibitors) with strategies able to enhance their cytotoxicity in the tumor bed, such as anti-KIR antibodies. The innovative aspect of this project relies on first driving NK cells to the tumor, and then activating them in the tumor battlefield. This project will provide a cutting edge approach to fully exploit the anti-tumor properties of NK cells in the clinic and establish the proof of concept for setting up novel NK-based clinical trials.