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.

• Authors: Takeshi Sugio, Kohta Miyawaki, Koji Kato, Kensuke Sasaki, Kyohei Yamada, Javeed Iqbal, Toshihiro Miyamoto, Koichi Ohshima, Takahiro Maeda, Hiroaki Miyoshi, Koichi Akashi
• Journal: Blood advances (Blood Adv) Vol. 2 Issue 17 Pg. 2242-2252 (09 11 2018) ISSN: 2473-9537 [Electronic] United States
• PMID: 30194138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents, Immunological
• IDO1 protein, human
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• PDCD1LG2 protein, human
• Programmed Cell Death 1 Ligand 2 Protein

Topics

• Antineoplastic Agents, Immunological (therapeutic use)
• B-Lymphocytes (immunology)
• Dendritic Cells (immunology)
• Female
• Fluorescent Antibody Technique
• Gene Expression Profiling
• Humans
• Immune System (cytology)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (metabolism)
• Lymphocytes, Tumor-Infiltrating
• Lymphoma, T-Cell, Peripheral (diagnosis, drug therapy, pathology)
• Male
• Middle Aged
• Prognosis
• Programmed Cell Death 1 Ligand 2 Protein (metabolism)
• Treatment Outcome