B Cells and Ectopic Follicular Structures: Novel Players in Anti-Tumor Programming with Prognostic Power for Patients with Metastatic Colorectal Cancer.
Meshcheryakova A, Tamandl D, Bajna E, Stift J, Mittlboeck M, Svoboda M, Heiden D, Stremitzer S, Jensen-Jarolim E, Grunberger T, Bergmann M, Mechtcheriakova D. B cells and ectopic follicular structures: novel players in anti-tumor programming with prognostic power for patients with metastatic colorectal cancer. (2014) PLoS One 9: e99008. 10.1371/journal.pone.0099008 [doi];PONE-D-14-04301 [pii].
For the last few years, understanding the relationship between tumor characteristics and local immune response has gained increasing attention. In contrast to T cells and TAMs, the functional role of tumor/stroma infiltrating B cells and the B-cell-driven machinery underlying pro- versus anti-tumor programming of neoplastic tissues is less understood. Important aspect linking B cell biology and tumor microenvironment is based on the discovery of germinal center (GC)-like structures outside of secondary lymphoid organs. Apart from benign tissues, ectopic follicular structures (or tertiary lymphoid structures) have been reported in some types of solid tumors, thus suggesting class switching of immunoglobulins and somatic hypermutation events to take place locally under the control of activation-induced cytidine deaminase (AID).
Given the multifaceted roles of B-cell-driven responses, we aimed to elucidate the immunological imprint of B lymphocytes at the metastatic site in the liver of patients with colorectal cancer at advanced stage, the interrelation between B cells and macrophages, and their prognostic relevance. Why this is of relevance:
- Remarkably limited information is available regarding biological mechanisms that determine the prognosis of this disease and could be considered as entry points for novel therapeutic interventions.
- There are no clinical parameters available to estimate survival prognosis of patients after liver resection.
- There are puzzling evidences to consider metastatic colorectal cancer as an immunogenic cancer type.
The microscopy-based imaging platform was used for automated scanning of large-scale tissue sections of patients with colorectal cancer metastases in the liver (n=65) and subsequent computerized quantitative analyses of immune cells at metastatic area, named immunological imprint. We reported for the first time that B cells and, strikingly, functionally active, AID-positive ectopic lymphoid structures were accumulated at the tumor – liver border within the metastatic margin of 1 mm only. Furthermore, the data suggest that as more B lymphocytes are present at the border as better the prognosis for the patient. Taken together, we nominate the magnitude of B lymphocytes, including those organized in ectopic follicles, as novel prognostic marker which is superior to any clinicopathological parameter. Findings emphasize anti-tumoral role of B cell-driven mechanism(s) and thus indicate a new way of thinking about potential treatment strategies for patients with metastatic colorectal cancer.
The work was done by Anastasia Meshcheryakova and Molecular Systems Biology and Pathophysiology Team (Head Diana Mechtcheriakova) in collaboration with surgical oncologists and pathologists of the Medical University.
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