Clinicopathological Significance of Tumor-Infiltrating T Lymphocytes and Macrophages in Primary Large B-Cell Lymphoma of Immune-Privileged Sites

Immune-privileged large B-cell lymphomas (IP-LBCLs), comprising primary central nervous system lymphoma (PCNS-LBCL), primary vitreoretinal lymphoma (PVR-LBCL), and primary testicular lymphoma (PT-LBCL), originate in sites with limited immune surveillance. Owing to their rarity, the prognostic implications of the tumor microenvironment in IP-LBCLs remain unclear, warranting further investigation. This study evaluated 109 IP-LBCL cases (PCNS-LBCL, n=87; PT-LBCL, n=22; six cases of PVR-LBCL excluded) using multiplex immunohistochemistry on tissue microarrays, along with clinicopathological analysis. Immune cell infiltration, tumor major histocompatibility complex (MHC) class I, and programmed death ligand-1 (PD-L1) expression, and their associations with clinical outcomes, were evaluated. PT-LBCL demonstrated higher infiltration of all tumor-infiltrating T lymphocyte (TIL) subsets than PCNS-LBCL (all p<0.05). Elevated CD4⁺ and CD8⁺ T-cell levels correlated with prolonged progression-free survival (PFS) (both p<0.05). M1 macrophage infiltration was associated with improved PFS (p=0.005) and independently predicted a favorable prognosis (hazard ratio = 0.49, p=0.041). Loss of MHC class I expression was more frequent in PT-LBCL than in PCNS-LBCL (77.3% vs. 9.2%; p<0.001). TIL infiltration predicted improved PFS only when the tumor MHC class I was preserved. Moreover, programmed death protein-1 (PD-1)⁺ TILs and tumor PD-L1 expression were associated with prognosis in conjunction with various clinicopathological variables. These findings highlight the favorable prognostic role of TILs and M1 macrophages, and underscore the complex immune-tumor interactions in IP-LBCLs, despite their origin in immune-privileged sites.