Yun-Li Xie,1,2,* Long-Feng Ke,3,* Wen-Wen Zhang,1,* Fu Kang,1 Shu-Yi Lu,2 Chen-Yu Wu,2 Huan-Huan Zhu,2 Jian-Chao Wang,1,* Gang Chen,1 Yan-Ping Chen1,* 

1Department of Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 2The School of Basic Medical Sciences, Fujian Medical University, and Department of Pathology, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 3Department of Molecular Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yan-Ping Chen, Jian-Chao Wang, Department of Pathology of Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, People’s Republic of China, Tel +86 0591-83660063, Fax +860591-62752890, Email kelf2006@126.com; jiancwang1989@163.com

Introduction: The tumor microenvironment (TME) influences diffuse large B-cell lymphoma (DLBCL) progression, but the prognostic roles of tumor-infiltrating T-lymphocytes (TIL-T), tumor-associated macrophages (TAMs), and PD-L1 remain undefined. This study investigates the clinicopathological associations and prognostic impacts of TIL-T, TAMs, and PD-L1 expression in DLBCL.
Methods: This retrospective study evaluated 89 primary DLBCL cases, integrating clinicopathological data with automated immunohistochemical quantification of CD3, CD8, FOXP3, CD163, and PD-L1 expression in tumor hotspots and microenvironmental compartments. Prognostic associations of TIL-T, TAMs, and PD-L1 expression with PFS and OS were analyzed via Kaplan-Meier methods and Cox regression.
Results: High CD3+ infiltration correlated with lower Ki-67 expression, while elevated FOXP3+ levels linked to improved Eastern Cooperative Oncology Group Performance Status (ECOG). CD163+ TAMs varied by NCCN-IPI risk, ECOG, and cell of origin. Neoplastic PD-L1 (nPD-L1) positivity associated with higher NCCN-IPI scores, CD3+ T-cell infiltration, and CD163+ TAM enrichment. Microenvironmental PD-L1 (mPD-L1) correlated with age, ECOG, B symptoms, and infiltration of all T-cell subsets and TAMs. Survival analysis revealed prolonged overall survival (OS) with high CD3+, CD8+, FOXP3+ TIL-T, CD163+ TAMs, or mPD-L1 positivity, while progression-free survival (PFS) improved with CD3+ infiltration and mPD-L1. Univariate analysis identified B symptoms, extranodal involvement, and low TIL-T levels as OS risks, whereas ECOG 0 and mPD-L1+ were protective. Multivariate modeling confirmed B symptoms, extranodal disease, and CD3+ TIL-T as independent OS predictors; CD3+ TIL-T and B symptoms independently impacted PFS.
Discussion: The TME plays a crucial role in the biological behavior of DLBCL, particularly because TIL-T and TAMs are significantly associated with patient survival outcomes. These cell types may serve as critical biomarkers and provide novel immunotherapy targets in DLBCL.

Keywords: diffuse large B-cell lymphoma, tumor microenvironment, tumor-infiltrating lymphocytes, tumor-associated macrophages, programmed death-ligand 1