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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, Grünberger T, Bergmann M, Mechtcheriakova D - PLoS ONE (2014)

Bottom Line: Strikingly, functionally active, activation-induced cytidine deaminase (AID)-positive ectopic lymphoid structures were found to be assembled within the metastatic margin.In contrast, CD68 staining-derived data set did not show an association with clinical outcome.Findings emphasize anti-tumoral role of B cell-driven mechanism(s) and thus indicate a new way of thinking about potential treatment strategies for CRCLM patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

ABSTRACT
Remarkably limited information is available about biological mechanisms that determine the disease entity of metastatic colorectal cancer in the liver (CRCLM) with no good clinical parameters to estimate prognosis. For the last few years, understanding the relationship between tumor characteristics and local immune response has gained increasing attention. Given the multifaceted roles of B-cell-driven responses, we aimed to elucidate the immunological imprint of B lymphocytes at the metastatic site, the interrelation with macrophages, and their prognostic relevance. Here we present novel algorithm allowing to assess a link between the local patient-specific immunological capacity and clinical outcome. The microscopy-based imaging platform was used for automated scanning of large-scale tissue sections and subsequent qualitative and quantitative analyses of immune cell subtypes using lineage markers and single-cell recognition strategy. Results indicate massive infiltration of CD45-positive leukocytes confined to the metastatic border. We report for the first time the accumulation of CD20-positive B lymphocytes at the tumor-liver interface comprising the major population within the large CD45-positive aggregates. Strikingly, functionally active, activation-induced cytidine deaminase (AID)-positive ectopic lymphoid structures were found to be assembled within the metastatic margin. Furthermore, the CD20-based data set revealed a strong prognostic power: patients with high CD20 content and/or ectopic follicles had significantly lower risk for disease recurrence as revealed by univariate analysis (p<0.001 for both) and in models adjusted for clinicopathological variables (p<0.001 and p = 0.01, respectively), and showed prolonged overall survival. In contrast, CD68 staining-derived data set did not show an association with clinical outcome. Taken together, we nominate the magnitude of B lymphocytes, including those organized in ectopic follicles, as novel prognostic marker which is superior to clinicopathological parameters. Findings emphasize anti-tumoral role of B cell-driven mechanism(s) and thus indicate a new way of thinking about potential treatment strategies for CRCLM patients.

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Prognostic effect of ectopic follicular structures allocated at the tumor – liver border.Kaplan-Meier estimates for patients stratification based on the ectopic follicle score at the border (a–c). Kaplan-Meier curves for RFS for panel I, panel II, and panel I+II show patient stratification into low (high number of follicular structures), intermediate (low number of follicular structures) and high risk (no follicular structures) groups; p value of the log-rank trend test is indicated. Panel I: low risk n = 5, intermediate risk n = 7, high risk n = 2; panel II: low risk n = 16, intermediate risk n = 17, high risk n = 18; panel I+II: low risk n = 21, intermediate risk n = 24, high risk n = 20. (d) Comparative assessment of contribution of no, low, and high ectopic follicle score to the total quantity for patient sub-groups without (No) and with (Yes) disease recurrence as estimated at the time point of 24 months where no censoring has occurred; p value of chi-square trend test is shown.
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pone-0099008-g005: Prognostic effect of ectopic follicular structures allocated at the tumor – liver border.Kaplan-Meier estimates for patients stratification based on the ectopic follicle score at the border (a–c). Kaplan-Meier curves for RFS for panel I, panel II, and panel I+II show patient stratification into low (high number of follicular structures), intermediate (low number of follicular structures) and high risk (no follicular structures) groups; p value of the log-rank trend test is indicated. Panel I: low risk n = 5, intermediate risk n = 7, high risk n = 2; panel II: low risk n = 16, intermediate risk n = 17, high risk n = 18; panel I+II: low risk n = 21, intermediate risk n = 24, high risk n = 20. (d) Comparative assessment of contribution of no, low, and high ectopic follicle score to the total quantity for patient sub-groups without (No) and with (Yes) disease recurrence as estimated at the time point of 24 months where no censoring has occurred; p value of chi-square trend test is shown.

Mentions: Next, we raised the question whether the magnitude of follicles developed within the border, designated as ectopic follicle score, is associated with clinical outcome. A higher score for ectopic follicular structures at the tumor – liver border showed significant better prognostic effect on RFS for patient samples from panel I and panel II when analysed individually and in combination (Table S5; univariate cox regression; panel I: HR = 0.145, 95% CI: 0.029–0.729, p = 0.019; panel II: HR = 0.575, 95% CI: 0.387–0.856, p = 0.006; panel I+II: HR = 0.520, 95% CI: 0.354–0.765, p<0.001). Figure 5 illustrates the results of the log-rank test for RFS showing significant patient stratification into low, intermediate, and high-risk groups (panel I, log-rank test: p = 0.009; panel II, log-rank test: p = 0.005; panel I+II, log-rank test: p<0.001). Additionally, a significant shift was seen towards a higher follicle score for patients of panel II without disease recurrence (no event before 24 months) in comparison to those with a disease recurrence before 24 months (p = 0.036; Figure 5, d).


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, Grünberger T, Bergmann M, Mechtcheriakova D - PLoS ONE (2014)

Prognostic effect of ectopic follicular structures allocated at the tumor – liver border.Kaplan-Meier estimates for patients stratification based on the ectopic follicle score at the border (a–c). Kaplan-Meier curves for RFS for panel I, panel II, and panel I+II show patient stratification into low (high number of follicular structures), intermediate (low number of follicular structures) and high risk (no follicular structures) groups; p value of the log-rank trend test is indicated. Panel I: low risk n = 5, intermediate risk n = 7, high risk n = 2; panel II: low risk n = 16, intermediate risk n = 17, high risk n = 18; panel I+II: low risk n = 21, intermediate risk n = 24, high risk n = 20. (d) Comparative assessment of contribution of no, low, and high ectopic follicle score to the total quantity for patient sub-groups without (No) and with (Yes) disease recurrence as estimated at the time point of 24 months where no censoring has occurred; p value of chi-square trend test is shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048213&req=5

pone-0099008-g005: Prognostic effect of ectopic follicular structures allocated at the tumor – liver border.Kaplan-Meier estimates for patients stratification based on the ectopic follicle score at the border (a–c). Kaplan-Meier curves for RFS for panel I, panel II, and panel I+II show patient stratification into low (high number of follicular structures), intermediate (low number of follicular structures) and high risk (no follicular structures) groups; p value of the log-rank trend test is indicated. Panel I: low risk n = 5, intermediate risk n = 7, high risk n = 2; panel II: low risk n = 16, intermediate risk n = 17, high risk n = 18; panel I+II: low risk n = 21, intermediate risk n = 24, high risk n = 20. (d) Comparative assessment of contribution of no, low, and high ectopic follicle score to the total quantity for patient sub-groups without (No) and with (Yes) disease recurrence as estimated at the time point of 24 months where no censoring has occurred; p value of chi-square trend test is shown.
Mentions: Next, we raised the question whether the magnitude of follicles developed within the border, designated as ectopic follicle score, is associated with clinical outcome. A higher score for ectopic follicular structures at the tumor – liver border showed significant better prognostic effect on RFS for patient samples from panel I and panel II when analysed individually and in combination (Table S5; univariate cox regression; panel I: HR = 0.145, 95% CI: 0.029–0.729, p = 0.019; panel II: HR = 0.575, 95% CI: 0.387–0.856, p = 0.006; panel I+II: HR = 0.520, 95% CI: 0.354–0.765, p<0.001). Figure 5 illustrates the results of the log-rank test for RFS showing significant patient stratification into low, intermediate, and high-risk groups (panel I, log-rank test: p = 0.009; panel II, log-rank test: p = 0.005; panel I+II, log-rank test: p<0.001). Additionally, a significant shift was seen towards a higher follicle score for patients of panel II without disease recurrence (no event before 24 months) in comparison to those with a disease recurrence before 24 months (p = 0.036; Figure 5, d).

Bottom Line: Strikingly, functionally active, activation-induced cytidine deaminase (AID)-positive ectopic lymphoid structures were found to be assembled within the metastatic margin.In contrast, CD68 staining-derived data set did not show an association with clinical outcome.Findings emphasize anti-tumoral role of B cell-driven mechanism(s) and thus indicate a new way of thinking about potential treatment strategies for CRCLM patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

ABSTRACT
Remarkably limited information is available about biological mechanisms that determine the disease entity of metastatic colorectal cancer in the liver (CRCLM) with no good clinical parameters to estimate prognosis. For the last few years, understanding the relationship between tumor characteristics and local immune response has gained increasing attention. Given the multifaceted roles of B-cell-driven responses, we aimed to elucidate the immunological imprint of B lymphocytes at the metastatic site, the interrelation with macrophages, and their prognostic relevance. Here we present novel algorithm allowing to assess a link between the local patient-specific immunological capacity and clinical outcome. The microscopy-based imaging platform was used for automated scanning of large-scale tissue sections and subsequent qualitative and quantitative analyses of immune cell subtypes using lineage markers and single-cell recognition strategy. Results indicate massive infiltration of CD45-positive leukocytes confined to the metastatic border. We report for the first time the accumulation of CD20-positive B lymphocytes at the tumor-liver interface comprising the major population within the large CD45-positive aggregates. Strikingly, functionally active, activation-induced cytidine deaminase (AID)-positive ectopic lymphoid structures were found to be assembled within the metastatic margin. Furthermore, the CD20-based data set revealed a strong prognostic power: patients with high CD20 content and/or ectopic follicles had significantly lower risk for disease recurrence as revealed by univariate analysis (p<0.001 for both) and in models adjusted for clinicopathological variables (p<0.001 and p = 0.01, respectively), and showed prolonged overall survival. In contrast, CD68 staining-derived data set did not show an association with clinical outcome. Taken together, we nominate the magnitude of B lymphocytes, including those organized in ectopic follicles, as novel prognostic marker which is superior to clinicopathological parameters. Findings emphasize anti-tumoral role of B cell-driven mechanism(s) and thus indicate a new way of thinking about potential treatment strategies for CRCLM patients.

Show MeSH
Related in: MedlinePlus