The pd‐l1/pd‐1 axis blocks neutrophil cytotoxicity in cancer

Abstract

The PD‐L1/PD‐1 axis mediates immune tolerance and promotes tumor growth and progression via the inhibition of anti‐tumor immunity. Blocking the interaction between PD‐L1 and PD‐ 1 was clinically shown to be beneficial in maintaining the anti‐tumor functions of the adaptive immune system. Still, the consequences of blocking the PD‐L1/PD‐1 axis on innate immune responses remain largely unexplored. In this context, neutrophils were shown to consist of distinct subpopulations, which possess either pro‐ or anti‐tumor properties. PD‐L1‐expressing neutrophils are considered pro‐tumor as they are able to suppress cytotoxic T cells and are propagated with disease progression. That said, we found that PD‐L1 expression is not limited to tumor promoting neutrophils, but is also evident in anti‐tumor neutrophils. We show that neutrophil cytotoxicity is effectively and efficiently blocked by tumor cell‐expressed PD‐1. Furthermore, the blocking of either neutrophil PD‐L1 or tumor cell PD‐1 maintains neutrophil cytotoxicity. Importantly, we show that tumor cell PD‐1 blocks neutrophil cytotoxicity and promotes tumor growth via a mechanism independent of adaptive immunity. Taken together, these findings highlight the therapeutic potential of enhancing anti‐tumor innate immune responses via blocking of the PD‐L1/PD‐1 axis.