PD-L1-positive circulating endothelial progenitor cells associated with immune response to PD-1 blockade in patients with head and neck squamous cell carcinoma

A number of the inhibitors against programmed death protein 1 (PD-1) have been approved to treat recurrent or metastatic squamous cell carcinoma of head and neck (HNSCC). The interaction between PD-1 and its ligand (PD-L1) serves as an immune checkpoint that governs cytotoxic immune effectors against tumors. Numerous clinical trials of PD-1/PD-L1 inhibitors have so far been discordant about having sufficient PD-L1 expression in the tumor as a prerequisite for a successful anti-PD-1 treatment. On the other hand, vascular endothelial cells modulate immune activities through PD-L1 expression, and thus it is possible that the expressions of circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CPCs) could affect antitumor immunity as well as neoangiogenesis. Here we investigated the potential involvement of PD-L1⁺ CECs and PD-L1⁺ CPCs in PD-1 blockade treatments for HNSCC patients. We measured CD8⁺ T cells, CECs, and CPCs in the peripheral blood of the HNSCC patients treated by anti-PD-1 therapies. We found that their PD-L1⁺ CPC expression before anti-PD1 therapies was strongly correlated with treatment responses and overall survival. Moreover, if the first infusion of PD-1 inhibitors reduced ≥ 50% PD-L1⁺ CPCs, a significantly better outcome could be predicted. In these patients as well as in an animal model of oral cancer, Pd-l1⁺ CPC expression was associated with limited CD8⁺ T-cell infiltration into the tumors, and anti-PD-1 treatments also targeted Pd-l1⁺ CPCs and increased CD8⁺ T-cell infiltration. Our results highlight PD-L1⁺ CPC as a potential regulator in the anti-PD-1 treatments for HNSCC.