Tumor-infiltrating B cells producing antitumor active immunoglobulins in resected HCC prolong patient survival
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Stefan M. Brunner1, Timo Itzel2, Christoph Rubner1, Rebecca Kesselring1, Eva Griesshammer1, Matthias Evert2, Andreas Teufel3, Hans J. Schlitt1 and Stefan Fichtner-Feigl1,4
1Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
2Institute of Pathology, University Medical Center Regensburg, Regensburg, Germany
3Department of Internal Medicine I, University Medical Center Regensburg, Regensburg, Germany
4Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany
Stefan M. Brunner, email: [email protected]
Keywords: B cell, immune infiltrate, tumor microenvironment, gene expression, immunoglobulin
Received: March 22, 2017 Accepted: May 22, 2017 Published: August 09, 2017
Background & Aims: The immunological microenvironment of HCC influences patient outcome, however, the role of B cells remains unclear. This study investigated effects of local B-cell infiltration in HCC cohorts on patient survival and immunological and molecular tumor microenvironment.
Results: Unsupervised gene expression analysis of full cancer transcriptomes (N=2158) revealed a highly co-regulated immunological cluster in HCC that mainly contained immunoglobulin fragments. More specifically, in an independent patient cohort (N=242) that compares HCC with non tumorous liver tissue high expression of these B-cell associated genes was associated with better patient outcome (P=0.0149). Conclusively, the immunohistochemical analysis of another independent cohort of resected HCCs (N=119) demonstrated that infiltration of HCCs by CD20+ cells (P=0.004) and CD79a+ cells (P=0.038) at the infiltrative margin were associated with prolonged patient survival. Further, the immunoglobulin fragments that were identified in the gene expression analysis were detected at high levels in patients with dense B-cell infiltration.
Methods: Gene expression of 2 independent HCC tissue databases was compared using microarrays. Additionally, tissue of resected HCCs was stained for CD20, CD79a and immunoglobulins and analysed for the respective cell numbers separately for tumor, infiltrative margin and distant liver stroma. These findings were correlated with clinical data and patient outcome.
Conclusions: Infiltration of HCCs by B cells is associated with prolonged patient survival. Further, a distinct B-cell like immunoglobulin profile of HCCs was identified that goes along with better patient outcome. We suggest that B cells contribute to local tumor control by secreting increased levels of immunoglobulins with antitumor activity.
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