PD-L1/PD-1 AXIS INHIBITS NEUTROPHIL CYTOTOXICITY IN CANCER

Introduction

PD-L1/PD-1 axis is an important immune checkpoint pathway, which enhances tumor prosperity via the inhibition of anti-tumor immune cells. In the context of cancer, neutrophils consist of different subpopulation, which exert both pro- and anti-tumor properties. PD-L1^-expressing neutrophils are considered pro-tumor as they are associated with disease progression and are able to suppress anti-tumor T cells. This project gives a wider scope to the role of PD-L1 on neutrophils in cancer.

Results and discussion

Blocking of PD-L1/PD-1 axis in co-culture of only tumor cells and neutrophils, enhanced tumor cell susceptibility to neutrophil cytotoxicity. This suggests that the PD-1/PD-L1 axis is also important in the direct interaction of neutrophils with tumor cells.

Moreover, over-expression of PD-1 on tumor cells resulted in a more aggressive phenotype as the tumors grew faster and had a higher metastatic load. Then, a seeding assay was performed. Depletion of neutrophils in the control mice enhanced the seeding of tumor cells in the lungs and exhibited the protective role of neutrophils. In contrast, neutrophil depletion in PD-1 over expression-injected mice did not show any significant effect. These observations suggest that PD-1 expression on tumor cells can alter neutrophils function and inhibit their anti-tumor cytotoxicity.

Conclusion

This work provides a novel insight into the interaction of PD-L1 on neutrophils with PD-1 on tumor cells and shows that PD-L1/PD-1 axis is also critical for the direct cytotoxic functions of neutrophils.