Expression of immune checkpoint molecules programmed death protein 1, programmed death‐ligand 1 and inducible T‐cell co‐stimulator in mycosis fungoides and Sézary syndrome: association with disease stage and clinical outcome

BACKGROUND: The relationship between immune checkpoint status and disease outcome is a major focus of research in cutaneous T‐cell lymphoma (CTCL), a disfiguring neoplastic dermatological disorder. Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common types of CTCL. OBJECTIVES: The aim was to evaluate the immune checkpoint markers programmed death protein 1 (PD1), inducible T‐cell co‐stimulator (ICOS) and programmed death‐ligand 1 (PD‐L1) in skin biopsies from patients with CTCL relative to disease stage and overall survival. METHODS: This consecutive case series enrolled 47 patients: 57% had stage IA–IIA disease and 43% had stage IIB–IVA2 disease (including seven with SS). RESULTS: PD1, PD‐L1 and ICOS expression was seen in all biopsies. Notably, PD‐L1 was predominantly expressed on histiocytes/macrophages, but focal expression on CTCL cells was seen. High expression of either ICOS or PD‐L1 was associated with advanced‐stage disease (P = 0·007 for both) and with the appearance of large‐cell transformation (LCT), a histopathological feature associated with a poor prognosis (ICOS: P = 0·02; PD‐L1: P = 0·002). PD1 expression was not significantly associated with disease stage (P = 0·12) or LCT (P = 0·49), but expression was high in SS biopsies. A high combined checkpoint marker score (PD1, PD‐L1 and ICOS) was associated with advanced‐stage disease (P = 0·001), LCT (P = 0·021) and lower overall survival (P = 0·014). CONCLUSIONS: These findings demonstrate the existence of a complex immunoregulatory microenvironment in CTCL and support the development of immunotherapies targeting ICOS and PD‐L1 in advanced disease.