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The prognostic impact of the tumor microenvironment in diffuse large B-cell lymphoma has not been systematically assessed. We analyzed mRNA and antigen expression of monocytes, macrophages, lymphocytes, dendritic and natural killer cells in pretreatment tumor samples of patients with high-risk diffuse large B-cell lymphoma using gene expression microarray and immunohistochemistry. The patients were treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis. Of the studied markers for non-malignant inflammatory cells, CD68 expression and CD68+ macrophage counts correlated with favorable outcome. Five-year progression-free survival rates were 83% and 43% for the patients with high and low CD68 mRNA levels, respectively (P=0.007), while overall survival rates were 83% and 64%, respectively (P=ns). The patients with high CD68+ macrophage counts had better 5-year progression-free survival (74% versus 40%; P=0.003) and overall survival (90% versus 60%; P=0.009) than the patients with low macrophage counts. Low CD68+ macrophage count retained its prognostic impact on overall survival with age-adjusted International Prognostic Index [RR=5.0 (95% CI 1.024–19.088); P=0.017]. The findings were validated in three independent cohorts of patients treated with chemoimmunotherapy. In contrast, in patients treated with chemotherapy, high CD68+ macrophage count was associated with poor progression-free survival (40% versus 72%; P=0.021) and overall survival (39% versus 72%; P=0.015). Together, the data suggest that macrophages exhibit a dual, treatment-specific role in diffuse large B-cell lymphoma. For the patients treated with chemoimmunotherapy, high pretreatment CD68 mRNA levels and CD68+ macrophage numbers predict a favorable outcome.