T-Cell Receptor Clonotypes and Aggressive Subtypes in Cutaneous T-Cell Lymphoma.

Abstract

T-cell receptor (TCR) clonotype patterns across disease stages and histologic subtypes in mycosis fungoides (MF) and Sézary syndrome (SS) remain poorly characterized, limiting their use in risk stratification. To assess the association of TCR β (TCRB) and γ (TCRG) clonotypes with disease stage, folliculotropism, large-cell transformation, and overall survival (OS) as well as clonal abundance (percentage of total reads) with immune checkpoint expression. This retrospective cohort study conducted at City of Hope (Duarte, California) included patients with stage IA to IVB MF/SS who underwent TCR next-generation sequencing on lesional skin biopsy specimens collected between June 2020 to October 2024; duplicate samples were excluded. Analyses were performed from November 2024 to April 2025. Associations between clinical and genetic categorical variables were evaluated using the Fisher exact test. OS was analyzed using Kaplan-Meier estimates, with univariate and multivariable models applied to assess prognostic factors. Of the 125 patients (42 female [33.6%] and 74 male individuals [66.4%]; mean [SD] age, 62.4 [15.9] years) who underwent TCR sequencing, at least 1 clonal TCRB and/or TCRG gene segment was identified in 98 patients (78%). Clonal TCRB and TCRG segments were detected in 72 (57.6%) and 92 patients (73.6%), respectively. The clonal Vb20 segment was significantly associated with folliculotropism and concurrent large-cell transformation compared with classic MF/SS (7 of 17 [41%] vs 0 of 30 [0%]; P < .001), marginally significantly associated with advanced-stage MF/SS compared with early-stage MF (8 of 38 [21%] vs 0 of 34 [0%]; P = .01). Clonal Vg8 was significantly associated with advanced-stage MF/SS compared with early-stage MF (25 of 53 [47%] vs 8 of 39 [21%]; P = .01) and correlated with poorer OS. Additionally, the higher percentage of total reads for TCRG was positively correlated with increased expression of immune checkpoints programmed cell death 1 and inducible T-cell costimulator but not with programmed cell death ligand 1. This cohort study's analysis of TCRB and TCRG repertoires identified specific clonotypes that were associated with more aggressive subtypes and poorer survival in patients with MF/SS. Incorporating TCR sequencing into clinical practice may enhance risk stratification, enabling earlier identification of high-risk patients who could benefit from closer monitoring and timely implementation of more intensive treatment strategies in the disease course to improve clinical outcomes.