Prognostic implications of tumor-infiltrating macrophages, M2 macrophages, regulatory T-cells, and indoleamine 2,3-dioxygenase-positive cells in primary diffuse large B-cell lymphoma of the central nervous system

Abstract

Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive disease with a poor prognosis. The status of the tumor immune microenvironment in CNS-DLBCL remains unclear. We investigated the prognostic implications of tumor-associated macrophages (TAMs), regulatory T-cells (Tregs), and indoleamine 2,3-dioxygenase (IDO)+ cells in primary CNS-DLBCL (n = 114) by immunohistochemical analysis. The numbers of tumor-infiltrating immune cells, including CD68+ TAMs, CD163+ or CD204+ M2 macrophages, FOXP3+ Tregs, and IDO+ cells were all significantly lower in CNS-DLBCL versus systemic DLBCL (n = 165; all P < 0.001), but with little difference in the ratio of CD163+/CD68+ or CD204+/CD68+ cells. An increase in CD68+ cell numbers was significantly associated with prolonged progression-free survival (PFS) and overall survival in patients with CNS-DLBCL (P = 0.004 and 0.021, respectively). In contrast, an increase in CD204+ cell numbers or a higher ratio of CD204+/CD68+ cells was related to a shorter PFS (P = 0.020 and 0.063, respectively). An increase in IDO+ cell numbers was associated with a significantly longer PFS (P = 0.019). In combination, the status of low IDO+ cell numbers combined with low CD68+ cell numbers, high CD204+ cell numbers, or a high CD204+/CD68+ cell ratio all predicted poor PFS in multivariate analyses. This study showed that an increase in CD204+ cell numbers, suggestive of M2 macrophages, was associated with poor clinical outcome in CNS-DLBCL, whereas increased CD68+ or IDO+ cell numbers were related to a favorable prognosis. The analysis of tumor-infiltrating immune cells could help in predicting the prognosis of CNS-DLBCL patients and determining therapeutic strategies targeting tumor microenvironment.