PD-L1/PD-1 AXIS INHIBITS NEUTROPHIL CYTOTOXICITY IN CANCER Olga Yajuk, Maya Gershkovitz, Tanya Fainsod-Levy, Zvi Granot Developmental Biology and Cancer Research Hadassah Medical School, Israel

Blocking PD-L1 and/or PD-1 is therapeutically utilized for maintaining the anti-tumor functions of the adaptive immune system. However, the consequences of blocking the PD-L1/PD-1 axis on innate immune responses remains largely unexplored. In cancer, neutrophils were shown to consist of different subpopulations, which possess either pro- and anti-tumor properties. We found that PD-L1 expression is not limited to the tumor promoting neutrophil subset but is also evident in the anti-tumor neutrophil subset. In this study we evaluated the role played by PD-L1 in regulating anti-tumor neutrophil cytotoxicity. We show that neutrophil cytotoxicity is efficiently blocked by tumor cell expressed PD-1. Furthermore, blocking of either neutrophil PD-L1 or tumor cell PD-1 maintains neutrophil cytotoxicity and enhances tumor cell apoptosis. Importantly, we show that high tumor cell PD-1 levels block neutrophil cytotoxicity and promotes tumor growth regardless the adaptive immune system. Taken together, these findings highlight the therapeutic potential of enhancing anti-tumor innate immune responses via blocking of the PD-L1/PD-1 axis. In summary, this work provides a novel insight into the interaction of PD-L1 on neutrophils with PD-1 on tumor cells. It was seen that PD-1 level in tumor cells has a significant impact on the anti-metastatic function of neutrophils and show that PD-L1/PD-1 axis is also critical for the direct cytotoxic functions of neutrophils against tumor cells.