Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS

Abstract

Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma

“…8,15 A recent study demonstrated that PTCL-NOS cases classified as GATA3 expressing on a different platform trended toward poorer OS. 49 In contrast, PTCL-TBX21 had low genomic complexity and did not show prominent TS deletions and mutations. TP53 signaling was a primary target in .50% of PTCL-GATA3 cases by biallelic deletion/ mutation of TP53, CDKN2A/2B (p14 ARF /p16 INK4A ), or RB1.…”

Cytokine‐related genes play critical roles in extrafollicular growth of follicular lymphoma cells

“…Further analyses using multiplex IHC will be needed to delineate that point. It is known that the nCounter gene expression system can more adequately evaluate low‐level expression of genes than the microarray analysis used in this study 23,24 . Therefore, evaluation using the nCounter system may reveal important cytokines for FL.…”

“…It is known that the nCounter gene expression system can more adequately evaluate low-level expression of genes than the microarray analysis used in this study. 23,24 Therefore, evaluation using the nCounter system may reveal important cytokines for FL. Although we checked the expression of these cytokines with IHC analysis, we did not evaluate which cells produce them.…”

Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

“…Independent of EMT, several bioinformatic analyses have supported the role of immune cells and clinical outcomes [122,123,124,125,126,127,128,129,130]. This demonstrates the ability of this technology to identify signatures of immune cells in bulk tumor samples.…”