Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in the western world. It is an aggressive disease and rapidly fatal if left untreated. With immunochemotherapy, a combination of chemotherapy and CD20 antibody rituximab, 70% of the patients can be cured. DLBCL comprises several distinct molecular subgroups, which differ in the expression of specific gene signatures and in the oncogenic pathways involved, corresponding to discrete prognostic categories. Research on biological prognostic factors and targeted therapies is active and it is likely that in the near future the patients will be treated according to risk-adapted and biomarker driven therapies. The aim of this study was to identify novel prognostic factors in the immunochemotherapy era. The study population comprised tumor tissue, blood samples and clinical data of DLBCL patients treated with immunochemotherapy. Methods included immunohistochemistry, ELISA and gene expression microarrays. PKCβII is an enzyme involved in cellular proliferation and it is overexpressed in cancer, including DLBCL. We observed that the patients with high tumor PKCβII expression had poorer survival than the patients with low expression. Consistently, high PKCβII gene expression correlated with inferior survival in an independent patient set. PKCβII is also known for its ability to stimulate tumor angiogenesis. We found no association between tumor microvessel density and survival data. Vascular endothelial growth factor (VEGF) is a signalling protein which stimulates angiogenesis. It is overexpressed in cancer and essential in tumor growth and development. We observed that high pretreatment serum VEGF levels are associated with inferior survival after therapy. However, VEGF mRNA levels correlated neither with the survival nor the serum VEGF levels. Thus, it is possible that the serum VEGF is not derived from the tumor itself but may be a host response instead. Tumor associated macrophages (TAMs) reprogrammed by malignant cells are a major source of angiogenic factors. Also, mechanism of rituximab is partly mediated by macrophages. The function of TAMs is known to be controversial: they have both anti-tumor and pro-tumor features. In our study, tumor macrophage counts correlated with favorable outcome. The findings were validated in independent cohorts of immunochemotherapy-treated patients. In contrast, in patients treated with chemotherapy, high macrophage count was associated with inferior survival. We also measured serum levels of CCL18 and CD163, proteins commonly expressed in M2 type macrophages. A significant association with inferior survival and low CCL18 serum levels was observed. To summarize, high PKCβII expression, low tumor TAM content, high serum VEGF and low serum CCL18 levels serve as prognostic factors for inferior outcome in immunochemotherapy-treated DLBCL. Their use as prognostic biomarkers in the clinical setting, however, calls for further study. The results underline the complex biology of DLBCL and the interplay between the tumor microenvironment, host responses and the malignant cells.
|Place of Publication||Helsinki|
|Publication status||Published - 2016|
|MoE publication type||G5 Doctoral dissertation (article)|
Fields of Science
- 3122 Cancers