Peripheral T-cell lymphoma (PTCL) represents a highly heterogeneous group of non-Hodgkin's lymphomas, often with aggressive biological behaviour. CD30 serves as a pivotal surface antigen in PTCL, however, its biological functions and therapeutic potential warrant further investigation.
We analysed 415 de novo patients with PTCL including 314 in the training cohort and 101 in the validation cohort across 11 medical centres in China. Genomic and transcriptomic profiles were examined by DNA- and RNA-sequencing in 355 and 169 patients, respectively.
In both cohorts, CD30+ PTCL presented significantly increased frequencies of SETD2, STAT3, and PTPRS mutations. Therefore, three molecular subtypes with distinct biological signatures were identified, including the HMA subtype characterised by dysregulation of histone methylation and acetylation, the JNE subtype by alterations in JAK-STAT, Notch signalling pathway, and EBV infection, and the PCT subtype by mutations in phosphorylation, chromatin remodelling, and T-cell receptor-major histocompatibility complex interaction, with extracellular matrix enrichment. Clinically, the JNE subtype demonstrated inferior progression-free survival (PFS) and overall survival (OS), as compared to the HMA and PCT subtypes. Brentuximab vedotin (BV)-containing treatment was associated with improved PFS and OS in the JNE and PCT subtypes. Furthermore, gene expression profile analysis demonstrated underlying vulnerabilities for the HMA, JNE, and PCT subtypes to epigenome-targeting agents, JAK or PI3K inhibitors, and PD-1 inhibitors, respectively.
The molecular subtypes of CD30+ PTCL demonstrated prognostic significance and varied sensitivity to BV treatment. Our findings further elucidated molecular regulatory networks of CD30+ PTCL, providing potential co-targeted approaches for genotype-guided precision medicine in PTCL.
This study was supported by National Key R&D Program of China, National Natural Science Foundation of China, Clinical Research Plan of Shanghai Hospital Development Centre, Shanghai Clinical Research Centre for Cell Therapy, Shanghai Municipal Health Commission, and China Postdoctoral Science Foundation.
Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.

T cell lymphoma (TCL) is a highly heterogeneous group of diseases with a poor prognosis and low 5-year overall survival rate. The current therapeutic regimens have relatively low efficacy rates. Clinical studies of single-target chimeric antigen receptor T cell (CAR-T cell) therapy in T lymphocytes require large and multiple infusions, increasing the risks and cost of treatment; therefore, optimizing targeted therapy is a way to improve overall prognosis. Despite significant advances in bispecific CAR-T cell therapy to avoid antigen escape in treatment of B cell lymphoma, applying this strategy to TCL requires further investigation. Here, we constructed an alpaca nanobody (Nb) phage library and generated high-affinity and -specificity Nbs targeting CD30 and CD5, respectively. Based on multiple rounds of screening, bispecific NbCD30-CD5-CAR T cells were constructed, and their superior anti-tumor effect against TCL was validated in vitro and in vivo. Our findings demonstrated that Nb-derived bispecific CAR-T cells significantly improved anti-tumor efficacy in TCL treatment compared with single-target CAR-T cells and bispecific single chain variable fragment (scFv)-derived CAR-T cells. Because Nbs are smaller and less immunogenic, the synergistic effect of Nb-based bispecific CAR-T cells may improve their safety and efficacy in future clinical applications.
© 2023 The Authors.

Mast cells (MCs) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MCs occur in low abundance, which hampers their detailed molecular analysis. Here, we capitalized on the potential of induced pluripotent stem (iPS) cells to give rise to all cells in the body and established a novel and robust protocol for human iPS cell differentiation toward MCs. Relying on a panel of systemic mastocytosis (SM) patient-specific iPS cell lines carrying the KIT D816V mutation, we generated functional MCs that recapitulate SM disease features: increased number of MCs, abnormal maturation kinetics and activated phenotype, CD25 and CD30 surface expression and a transcriptional signature characterized by upregulated expression of innate and inflammatory response genes. Therefore, human iPS cell-derived MCs are a reliable, inexhaustible, and close-to-human tool for disease modeling and pharmacological screening to explore novel MC therapeutics.

Natural killer (NK)/T cell lymphoma is a highly aggressive subtype of non-Hodgkin lymphoma. The prognosis of patients with natural killer T cell lymphoma (NKTCL) remains poor. More potent treatment strategies are urgently needed to improve the survival of these patients with R/R NKTCL. CD30 expression has been reported to occur in about 40% of NK/T cell lymphoma. Brentuximab vedotin (BV), a monomethyl auristatin E conjugated CD30 antibody, targets CD30 to kill cancer cells. Therapeutic combination of BV and bendamustine has been shown to be highly effective in Hodgkin lymphoma. We investigated efficacy of BV in treating NKTCL as a single therapy, and in combination with bendamustine in vitro and in vivo. We determined CD30 expression levels in 6 NKTCL cell lines. The efficiency of lymphoma cell inhibition by BV correlates with CD30 expression. We also determined the efficacy of BV in combination with bendamustine and found synergistic effects with bendamustine in NKTCL. Combined BV and bendamustine treatment exerted synergistic antiproliferation effect and enhanced cell apoptotic in vitro and in vivo. Brentuximab vedotin and bendamustine synergistically arrested cell cycle at the G2/M phase in NKTCL cell lines. The combination of BV and bendamustine was demonstrated to synergistically damage DNA in NKTCL. This study provides a reference for possible application on using BV for the treatment of NKTCL, either as a single agent or in combination with bendamustine.© 2022 John Wiley & Sons Ltd.

Very few B cells in germinal centers (GCs) and extrafollicular (EF) regions of lymph nodes express CD30. Their specific features and relationship to CD30-expressing Hodgkin and Reed/Sternberg (HRS) cells of Hodgkin lymphoma are unclear but highly relevant, because numerous patients with lymphoma are currently treated with an anti-CD30 immunotoxin. We performed a comprehensive analysis of human CD30+ B cells. Phenotypic and IgV gene analyses indicated that CD30+ GC B lymphocytes represent typical GC B cells, and that CD30+ EF B cells are mostly post-GC B cells. The transcriptomes of CD30+ GC and EF B cells largely overlapped, sharing a strong MYC signature, but were strikingly different from conventional GC B cells and memory B and plasma cells, respectively. CD30+ GC B cells represent MYC+ centrocytes redifferentiating into centroblasts; CD30+ EF B cells represent active, proliferating memory B cells. HRS cells shared typical transcriptome patterns with CD30+ B cells, suggesting that they originate from these lymphocytes or acquire their characteristic features during lymphomagenesis. By comparing HRS to normal CD30+ B cells we redefined aberrant and disease-specific features of HRS cells. A remarkable downregulation of genes regulating genomic stability and cytokinesis in HRS cells may explain their genomic instability and multinuclearity.