Platelets Increase the Expression of PD-L1 in Ovarian Cancer

SIMPLE SUMMARY: One-third of patients with ovarian cancer have elevated platelet counts associated with a poor prognosis. We found that platelets increase the expression of immune checkpoint (PD-L1) in ovarian cancer in mice and patients. Reducing platelet counts or inhibiting platelet function reduced the expression of PD-L1 in tumors. We investigated the mechanism of platelet-induced PD-L1 and showed that platelets increase PD-L1 on cancer cells both directly (contact-dependent through NF-κB signaling) and indirectly (contact-independent via TFGβ released from platelets through TFGβR1/Smad signaling). Our results show that platelets dampen the antitumor immune response in the tumor microenvironment. Based on our preclinical results, we speculate that platelet counts might be a predictive biomarker for immunotherapy, i.e., patients with thrombocytosis respond better to anti-PD1/PDL-1 therapy. On the other hand, the use of aspirin or other antiplatelet reagents may impact the effectiveness of immunotherapy. These speculations need to be examined in clinical trials. ABSTRACT: The interactions between platelets and cancer cells activate platelets and enhance tumor growth. Platelets increase proliferation and epithelial–mesenchymal transition in cancer cells, inhibit anoikis, enhance the extravasation of cancer cells, and protect circulating tumor cells against natural killer cells. Here, we have identified another mechanism by which platelets dampen the immune attack on cancer cells. We found that platelets can blunt the antitumor immune response by increasing the expression of inhibitory immune checkpoint (PD-L1) on ovarian cancer cells in vitro and in vivo. Platelets increased PD-L1 in cancer cells via contact-dependent (through NF-κB signaling) and contact-independent (through TFGβR1/Smad signaling) pathways. Inhibition of NF-κB or TGFβR1 signaling in ovarian cancer cells abrogated platelet-induced PD-L1 expression. Reducing platelet counts or inhibiting platelet functions reduced the expression of PD-L1 in ovarian cancer. On the other hand, an increase in platelet counts increased the expression of PD-L1 in tumor-bearing mice.