Surface TREM2 on circulating M-MDSCs as a novel prognostic factor for adults with treatment-naïve diffuse large B-cell lymphoma

Experimental Hematology & Oncology

卷:12

Research

Ching-Fen Yang¹  Po-Shen Ko²  Yao-Chung Liu²  Chun-Kuang Tsai²  Hao-Yuan Wang³  Yi-Lin Chung⁴  Chien-Jung Li⁵  Fu-Chen Yang⁵  Nien-Jung Chen⁶ 

[1] Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;

[2] Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;

[3] Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;Program in Molecular Medicine, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan;

[4] Institute of Genome Sciences, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan;

[5] Institute of Microbiology and Immunology, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan;

[6] Program in Molecular Medicine, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan;Institute of Microbiology and Immunology, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan;

关键词: Arginase 1;    Cytotoxic T lymphocytes (CTLs);    Diffuse large B-cell lymphoma (DLBCL);    Monocytic myeloid-derived suppressor cells (M-MDSCs);    Triggering receptors expressed on myeloid cells 2 (TREM2);   

DOI  :  10.1186/s40164-023-00399-x

 received in 2022-11-23, accepted in 2023-03-27,  发布年份 2023

来源: Springer

【 摘 要 】

IntroductionCirculating monocytic myeloid-derived suppressive cells (M-MDSCs) are implicated as a poor prognostic factor and cause CAR T-cell failure in diffuse large B-cell lymphoma (DLBCL). Triggering receptors expressed on myeloid cells 2 (TREM2) are a transmembrane glycoprotein that polarize macrophages to anti-inflammation phenotype but have never been explored on M-MDSCs. This study aims to elucidate the expression and clinical impact of surface TREM2 on circulating M-MDSCs derived from DLBCL adults.MethodsThis prospective, observational study enrolled 100 adults with newly diagnosed and treatment-naïve DLBCL from May 2019 to October 2021. Human circulating M-MDSCs were obtained from freshly isolated peripheral blood, and each patient’s surface-TREM2 level on M-MDSCs was normalized via a healthy control at the same performance of flow-cytometry analysis. Murine MDSCs derived from bone marrow (BM-MDSCs) were adopted to assess the link between Trem2 and cytotoxic T lymphocytes.ResultsMore circulating M-MDSCs at diagnosis of DLBCL predicted worse progression-free (PFS) and overall survival (OS). Patients with higher IPI scores, bone marrow involvement, or lower absolute counts of CD4+ or CD8+ T cells in PB had significantly higher normalized TREM2 levels on M-MDSCs. Additionally, normalized TREM2 levels on M-MDSCs could be grouped into low (< 2%), medium (2–44%), or high (> 44%) levels, and a high normalized TREM2 level on M-MDSCs was proven as an independent prognostic factor for both PFS and OS via multivariate Cox regression analysis and associated with worst PFS and OS. Interestingly, normalized levels of surface TREM2 on M-MDSCs were negatively associated with absolute counts of PB CD8+ T cells and positively correlated with levels of intracellular arginase 1 (ARG1) within M-MDSCs. Wild-type BM-MDSCs had significantly higher mRNA levels of Arg1 and showed more prominent ability to suppress the proliferation of co-cultured CD8+ T cells than BM-MDSCs from Trem2 knockout mice, and the suppressive ability could be impaired by adding Arg1 inhibitors (CB1158) or supplementing L-arginine.ConclusionIn treatment-naïve DLBCL adults, a high surface-TREM2 level on circulating M-MDSCs is a poor prognostic factor for both PFS and OS and warrants further investigation for its potential as a novel target in immunotherapy.

【 授权许可】

CC BY   
© The Author(s) 2023

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