Among patients with mycosis fungoides (MF) and Sézary syndrome (SS), the T-cell receptor (TCR) clonal Vb20 segment was significantly associated with advanced-stage disease, folliculotropism with concurrent large-cell transformation, and poor overall survival, in a retrospective cohort study. In addition, the authors reported, the Vg8 clonotype was linked to advanced-stage MF/SS and poor overall survival.

Those are key findings from the study of 125 patients with MF/SS, which used next-generation sequencing (NGS) to determine whether specific TCR clonotypes are associated with disease progression and survival outcomes in MF/SS, the most common types of cutaneous T-cell lymphoma (CTCL).

“Testing for TCR clonotypes by NGS sequencing in CTCL may improve early and accurate disease stratification that helps tailor therapy to a patient’s risk profile and provides better monitoring of treatment responses,” the study’s corresponding author Christiane Querfeld, MD, PhD, professor of dermatology and dermatopathology at the City of Hope Cancer Center and Beckman Research Institute, Duarte, California, told Medscape Medical News. “Identifying specific clonotypes could help differentiate aggressive from indolent forms earlier, guiding personalized treatment. TCR sequencing could also detect new clonotypes that may evolve with treatment.”

For the study, which was published online in JAMA Dermatology on October 22, researchers retrospectively evaluated the medical records of 125 patients at the City of Hope with stage IA to IVB MF/SS who underwent TCR NGS on lesional skin biopsy specimens collected between June 2020 and October 2024. They used the Fisher exact test to evaluate associations between clinical and genetic categorical variables and Kaplan-Meier analysis to determine overall survival.

The mean age of patients was 62.4 years, 66.4% were male. Of the 125 patients who underwent TCR sequencing, at least one clonal TCRB (TCR beta) and/or TCRG (TCR gamma) gene segment was identified in 98 patients (78%). Specifically, clonal TCRB segments were detected in 72 patients (57.6%), and clonal TCRG segments were detected in 92 patients (73.6%).

The clonal Vb20 segment was significantly associated with folliculotropism and concurrent large-cell transformation when compared with classic MF/SS (7 of 17 [41%] vs 0 of 30; P < .001) and showed a marginally significant association with advanced-stage MF/SS compared with early-stage MF (8 of 38 [21%] vs 0 of 34; P = .01).

Similarly, the clonal Vg8 segment 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 was correlated with poorer overall survival.

“While our goal of the study was to identify specific TCR sequences that are aligned with subtypes of CTCL or specific features, the potential association between high clonal abundance (clonal burden) of disease and increased PD-1 expression is a significant finding because it suggests a more immunosuppressive tumor microenvironment in aggressive cases,” Querfeld explained. “High PD-1 expression on T cells typically signifies T-cell exhaustion, allowing large malignant clones to evade the immune response, and, therefore, promoting progression of disease.”

The study “suggests that pathology reports should eventually move beyond clone detected and instead include documentation on leading clonotypes and dominant clone frequency,” Cuong V. Nguyen, MD, and Joan Guitart, MD, of the Department of Dermatology, Northwestern University, Chicago, wrote in an accompanying editorial.

“Multi-institutional studies can help build databases that connect clonotype to clinicopathologic phenotypes,” they added. “As these databases expand, dermatopathologists can provide NGS reports like those seen in melanoma and other cancers and provide an interpretative comment that may be helpful in translating clonotype patterns into clinical risk profiles for the clinician.”

Asked to comment on the results, Shari Lipner, MD, PhD, associate professor of clinical dermatology at Weill Cornell Medicine, New York City, who was not affiliated with the study, told Medscape Medical News that the study highlights the use of TCR sequencing as both a diagnostic and prognostic tool in CTCL. “Incorporating TCR sequencing into CTCL management could help to individualize treatment strategies,” she said. “We may be able to better identify high-risk patients who may benefit from closer surveillance and timely initiation of systemic or targeted therapies.”

She added that prospective long-term studies are needed to corroborate these results. “Other unanswered questions are the mechanisms of T-cell receptors in immune evasion and their potential as therapeutic targets,” Lipner said.

The researchers acknowledged certain limitations of the analysis, including its retrospective design and the fact that some of the patients were assessed after treatment failure or relapse, “so prior therapies may have contributed to TCR expression patterns and immune checkpoint molecules,” they wrote.

In an interview, Querfeld added that while this investigation is the largest of its kind to date, additional work is needed to validate findings in a larger prospective study, “and to apply analysis in early-stage CTCL patients with the goal to translate results into standardized clinical tests, investigate the immunologic tumor microenvironment, and determine optimal methods for long-term monitoring, including for minimal residual disease.”

The research was supported by the National Cancer Institute. Querfeld reported receiving grants from the Leukemia Lymphoma Society during the conduct of the study as well as grants from Kyowa Kirin and personal fees from Helsinn, Citius Pharm, and SLAM BioTherapeutics outside the submitted work. Guitart reported receiving grants from Castle Biosciences. Lipner reported having no relevant disclosures.

Doug Brunk is a San Diego-based medical journalist.