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The expression of immune checkpoint proteins such as programmed cell death protein 1 ( PD ‐1) and its ligand ( PD ‐L1) has been shown to correlate with patient prognosis in many malignant cancers. The expression of  PD ‐L1 is controlled by c‐Myc; however, further upstream regulation of  PD ‐L1 expression is largely unknown. We have previously shown that atypical protein kinase C lambda/iota ( aPKC λ) phosphorylates the Forkhead box protein O1 (FoxO1) transcription factor at Ser218 to suppress its  DNA ‐binding ability, thereby regulating c‐Myc expression and controlling physiologic and pathologic endothelial proliferation. The presence of phosphorylation of FoxO1 at Ser218 (pSer218 FoxO1) in cutaneous angiosarcoma ( CAS ) strongly correlates with poor patient prognosis. Here, we reported that patients with  PD ‐L1 +  cells in  CAS  lesions showed significantly worse prognosis compared to those that were  PD ‐L1 − . Expression of  PD ‐L1 correlated with that of  aPKC λ or the presence of  pS er218FoxO1. Moreover, suppression of  aPKC λ expression or inhibition of its activity in  HUVEC s or  AS ‐M, an established human angiosarcoma cell line, resulted in decreased  PD ‐L1 expression. Our results suggest that combined treatment with immune checkpoint inhibitors and  aPKC λ inhibitors could be a novel treatment strategy for  CAS  patients.

Regulation of programmed cell death ligand 1 expression by atypical protein kinase C lambda/iota in cutaneous angiosarcoma