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

Importance: 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. Objectives: 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. Design, Setting, and Participants: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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.