Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial.
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.
Department of Oncology, Helsinki University Central Hospital Cancer Center, Finland Genome Scale Biology Program, University of Helsinki, Finland.
Sari
S
Riihijärvi
Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Norway.
Idun
I
Fiskvik
Department of Oncology, Helsinki University Central Hospital Cancer Center, Finland Genome Scale Biology Program, University of Helsinki, Finland.
Minna
M
Taskinen
Department of Oncology, Helsinki University Central Hospital Cancer Center, Finland Genome Scale Biology Program, University of Helsinki, Finland.
Heli
H
Vajavaara
Department of Oncology, Helsinki University Central Hospital Cancer Center, Finland Genome Scale Biology Program, University of Helsinki, Finland.
Maria
M
Tikkala
Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Norway.
Olav
O
Yri
Department of Pathology, Haartman Institute, University of Helsinki, Finland.
Marja-Liisa
ML
Karjalainen-Lindsberg
Department of Pathology, Oslo University Hospital, Norway.
Jan
J
Delabie
Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Norway Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway.
Erlend
E
Smeland
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway Department of Oncology, Oslo University Hospital, Oslo, Norway.
Harald
H
Holte
Department of Oncology, Helsinki University Central Hospital Cancer Center, Finland Genome Scale Biology Program, University of Helsinki, Finland sirpa.leppa@helsinki.fi.
Sirpa
S
Leppä
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate
D000911:Antibodies, Monoclonal