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*

Abstract

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. What is already known about this topic? Expression of immune checkpoint markers has been observed in many cancers. Immunotherapies targeting one or more immune checkpoint markers can be very effective. However, little is known about the immune checkpoint marker status in cutaneous T-cell lymphoma (CTCL), including the potential relationship between checkpoint marker expression and disease stage or survival. What does this study add? We show an association between checkpoint marker expression and disease outcomes in patients with mycosis fungoides and Sézary syndrome, the most common forms of CTCL. A combined checkpoint score predicts disease stage and survival better than individual scores. These findings support the development of immune checkpoint scores as prognostic indicators for CTCL. Further investigation of checkpoint inhibitor immunotherapies for patients with CTCL, especially combination therapies, may have clinical benefit.

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