An immunohistochemical classification panel for predicting molecular subtypes of mycosis fungoides with therapeutic implications

Summary: Abstract Body: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma, with wide variability in patient outcomes. This study aimed to develop an immunohistochemical (IHC) panel to predict molecular subtypes of MF and evaluate its therapeutic implications. Using single-cell RNA sequencing, we previously identified two molecular subtypes of MF, the central memory T cell (TCM) group and the cytotoxic effector memory T cell (TCyEM) group, which show distinct tumor microenvironment profiles and prognoses (Liu et al., Nature Communications, 2022). In this study, we developed an immunohistochemical (IHC) panel to identify these subtypes in paraffin tissue using antibodies targeting key differentially expressed genes: CD27 and TOX for TCM group, and GZMA and HOPX for TCyEM group. A total of 126 MF cases were included, with 69 having RNA-seq data to determine the molecular subtype and establish cut-off values for each IHC marker. The cut-off values (CD27 ≥ 0.5, TOX ≥ 0.5, GZMA ≥ 0.2, HOPX ≥ 0.1) were used to classify patients into three groups: TCM (n=35), TCyEM (n=70), and undetermined (n=21). The IHC panel identified TCM and TCyEM groups with high sensitivity (85%), and these subtypes showed a significant difference in progression-free survival (PFS) (P<0.001). In multivariate analysis, folliculotropism subtype and the TCM subtype, as determined by IHC, were independent adverse predictors of PFS (P=0.001), regardless of age, sex, stage, and large cell transformation. Additionally, retrospective analysis of clinical treatment regimens revealed that for the TCM group, treatment primarily with retinoids resulted in a longer time to next treatment (TTNT) (P=0.006). For the TCyEM group, interferon-based therapy maintained TTNT and offered better safety. Thus, the IHC classification panel will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials. Zhuojing Chen¹, Yang Wang¹ 1. Dermatology and Venereology, Peking University First Hospital, Beijing, Beijing, China. Translational Studies: Preclinical