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Peripheral T-Cell Lymphoma Study Spells Out Molecular, Microenvironment Subtypes

NEW YORK – A team from Shanghai Jiao Tong University's State Key Laboratory of Medical Genomics and other centers in China has used tumor DNA and RNA sequencing to track down distinct tumor- and microenvironment-based subtypes of peripheral T-cell lymphoma (PTCL), a heterogeneous form of non-Hodgkin lymphoma.

"Our findings highlight the potential clinical rationale of future precision medicine strategies that target both molecular and microenvironment alterations in PTCL," senior and corresponding author Wei-Li Zhao, a hematology researcher affiliated with Shanghai Jiao Tong University School of Medicine and the Franco-Chinese Research Center in Life Sciences and Genomics molecular pathology laboratory, and colleagues wrote in Cell Reports Medicine on Monday.

Using exome sequencing, the team initially profiled 101 PTCL samples, along with matched peripheral blood samples from 21 of the PTCL patients. Together with tumor RNA sequencing profiles and deep targeted capture sequencing on samples from another 120 PTCL cases, the exome sequence data pointed to four molecular subtypes and expression-based lymphoma microenvironment clusters.

"[W]e aimed to portray a comprehensive genomic landscape of mutations as well as establish a molecular stratification based on genetic signatures, biological alterations, and therapeutic responses, proposing four distinct subgroups of PTCL," the authors wrote, noting that the findings further "defined a microenvironment stratification derived from gene expression footprints of infiltrating immune cells and stromal components, which also reflected distinct biological features and clinical properties."

The researchers' results revealed four molecular subtypes marked by distinct tumor mutation, copy number, and expression profiles, potential targeted treatment vulnerabilities, and clinical features.

While the T1 molecular subtype was marked by mutations in the RHOA and TET2 genes, for example, the T2 subtype contained tumors with recurrent TET2 alterations in the absence of RHOA changes. On the other hand, the T3.1 subtype contained frequent histone modification gene alterations, whereas the T3.2 subtype was marked by mutations affecting immune-related genes — from the human leukocyte antigen (HLA) genes HLA-A and HLA-B to the JAK-STAT signaling pathway gene PTPN13.

Along with analyses on each of the molecular subgroups in relation to the established PTCL subtypes of "not otherwise specified" (NOS) PTCL, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma, the team used cell line experiments and patient-derived xenograft models in zebrafish to track treatment response patterns.

Moreover, the authors noted that a multicenter, randomized Phase II trial within each molecular subtype is currently ongoing.

When the investigators considered microenvironment subtypes, meanwhile, they saw four subtypes — dubbed Tfh-like, inflammatory, mesenchymal, and depleted — that showed distinct immune features and clinical outcomes, based on overall survival and progression-free survival data for 186 PTCL patients followed for a median of more than 3.6 years.

"[W]e obtained microenvironment evidence and established distinct immune-related [lymphoma microenvironment] subtypes in PTCL, simultaneously integrating malignant T-cell populations and microenvironment components into the prognosis and treatment of the disease" the authors reported, though they cautioned that "further validation by pathological immunohistochemistry" will be needed to validate the study's RNA-seq findings.