PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer.

Background: Programmed cell death ligand 1 (PD-L1) expression on immune cells is correlated with the efficacy of immune checkpoint inhibitor (ICI) therapy in various types of cancer. Platelets are important components of the tumour microenvironment (TME) and are widely involved in the development of many types of cancer including colorectal cancer (CRC). However, the role of PD-L1 positive platelets in ICI therapy for CRC remains unknown. We hypothesized that PD-L1 positive platelets trigger and sustain CRC immunosuppression.

Methods: The functional depletion effects of PD-L1 positive platelets on TME and immune cells were measured via western blotting, immunofluorescence staining, qRT-PCR, ELISpot and flow cytometry. In vivo, CD274 knockout (KO), CD8a KO, platelet-specific KO (PF4-Cre-Hsp90b1) mouse models and a subcutaneous tumour model treated with aspirin and PD-L1 mAb were established in C57BL/6 N mice.

Results: We found that PD-L1 positive platelets are correlated with a poor prognosis, CD8 + T cell exhaustion and serve as a novel noninvasive biomarker for predicting immunotherapy efficacy in patients with CRC. The transfer of PD-L1 from tumour cells to platelets in the TME depends on direct cell contact via the fibronectin-1/GPIbα/integrin α5β1 pathway. In turn, platelets can also induce PD-L1 expression on cancer cells. Animal experiments revealed that antiplatelet pharmacological agents and genetic knockout of platelets potentiated the antitumour effect of the PD-L1 mAb treatment in a CD8 + T cell dependent manner.

Conclusions: Our data suggest that PD-L1 positive platelets suppress CD8 + T cell immunity. Clinical combination treatment with ICIs and antiplatelet agents may be an effective therapeutic strategy for treating CRC.