Prognostic values of circulating TREM2+ and ARG1+ Mreg cells in adults with treatment‐naïve diffuse large B‐cell lymphoma

Abstract

Introduction: Novel Trem2+ (triggering receptor expressed on myeloid cells 2) and Arg1+ (arginase 1) regulatory myeloid cells (Mreg) that lead to the dysfunction of CD8+ T cells and facilitate tumor growth were recently discovered in a murine cancer model by Yonatan Katzenelenbogen et al. However, as the roles of Mreg cells have never been examined in human cancer patients, we aim to elucidate the clinical impact of circulating Mreg cells on patients with treatment-naive B-cell NHL, especially focusing on DLBCL. Methods: This prospective, observational study enrolled 102 adults with newly diagnosed and treatment-naïve B-cell NHL, including 62 DLBCL, 25 FL (4 grade 3B), 4 MCL, 4 MZL, 2 LPL, 2 BL, and 3 mature B-cell neoplasms, from December 2020 to November 2022. We obtained human circulating TREM2+ and ARG1+ Mreg cells from freshly isolated peripheral blood and calculated their percentages among CD45+ and CD15- cells by flow-cytometry analysis. Non-stain (NS) and fluorescence minus one (FMO) controls were used for gating positive levels of surface TREM2 and intracellular ARG1, respectively. Results: Among 102 patients with B-cell NHL, those with high-risk IPI had significantly higher percentages of circulating Mreg cells than patients with intermediate or low-risk IPI (5.46% vs. 1.71% vs. 0.63%, P H vs. L < 0.001, P H vs. I = 0.032, P I vs. L = 0.005); patients with aggressive subtypes (including grade-3B FL) had significantly higher percentages of circulating Mreg cells than patients with indolent subtypes (1.89% vs. 0.93%, P = 0.023). For 62 DLBCL patients, those with high IPI risk (9.18% vs. 1.25%, P < 0.001), bulky mass ≥ 7.5 cm (5.08% vs. 1.18%, P = 0.057), or DEL (5.13% vs. 1.21%, P = 0.036) had significantly higher percentages of circulating Mreg cells (Figures A–F). More importantly, DLBCL patients with circulating Mreg cells ≥4.5% had significantly worse PFS and OS than those with Mreg cells <4.5% after a median follow-up of 14 months (Figures G and H); when utilizing multivariate Cox regression analysis, “circulating Mreg cells ≥4.5%” remained an independent prognostic factor for both PFS and OS after adjusting for confounding factors, including age, sex, high-risk IPI, bulky mass ≥7.5 cm, BM involvement, non-GCB type, and DEL. The research was funded by: The research was funded by grants from: (1) the Taiwan Ministry of Science and Technology (MOST 111-2314-B-075-037), (2) Taipei Veterans General Hospital (V110B-012), (3) the Chong Hin Loon Memorial Cancer and Biotherapy Research Center, (4) the Melissa Lee Cancer Foundation, and (5) the Taiwan Clinical Oncology Research Foundation. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.