For a study, it was determined that in cutaneous T-cell lymphoma (CTCL), a disfiguring neoplastic dermatological illness, the link between immune checkpoint status and disease outcome was a primary focus of research. The two most frequent kinds of CTCL were mycosis fungoides (MF) and Sézary syndrome (SS). The researchers sought to determine how the immunological checkpoint markers programmed death protein 1 (PD1), inducible T-cell costimulator (ICOS), and programmed death-ligand 1 (PD-L1) correlated with disease stage and overall survival in CTCL patients’ skin samples. A total of 47 patients were enrolled in the case series, with 57% having stage IA-IIA disease and 43% having stage IIB-IVB disease, including 7 with SS. All samples showed PD1, PD-L1, and ICOS expression. PD-L1 was primarily expressed on histiocytes/macrophages, but there was also the focal expression on CTCL cells. High ICOS or PD-L1 expression was linked to advanced-stage disease (both P=0.007) and the presence of large cell transformation (LCT), a histopathological hallmark linked to a poor prognosis (ICOS: P=0.02; PD-L1: P=0.002). Although PD1 expression was not linked with disease stage (P=0.12) or LCT (P=0.49), it was abundant in SS tissues. Advanced-stage disease (P=0.001), LCT (P=0.021), and shorter overall survival (P=0.014) were all linked to a high combined checkpoint marker score (PD-1, PD-L1, and ICOS). The results assisted the development of immunotherapies targeting ICOS and PD-L1 in advanced CTCL by demonstrating the existence of a complex immunoregulatory milieu.