Abstract
Background & AimsThe 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.ResultsUnsupervised 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.MethodsGene 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.ConclusionsInfiltration 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.
Highlights
Hepatocellular carcinoma (HCC) is the most frequent liver cancer entity worldwide with an increasing incidence [1, 2]
Infiltration of HCCs by B cells is associated with prolonged patient survival
We suggest that B cells contribute to local tumor control by secreting increased levels of immunoglobulins with antitumor activity
Summary
Hepatocellular carcinoma (HCC) is the most frequent liver cancer entity worldwide with an increasing incidence [1, 2]. For the majority of HCC patients outcome remains poor due to tumor recurrence and the fact www.impactjournals.com/oncotarget that many patients present with disease that is too advanced for curative surgery or liver transplantation [4]. Our group has demonstrated that tumorinfiltrating, interleukin-33-producing CD8+ T cells in resected HCC prolong patient survival [6] These CD8+ T cells have been characterized as highly effective, cytotoxically active CD8+CD62L-KLRG1+CD107a+ effector-memory cells producing IL-33 [6]. These tumor antigen specific cytotoxic CD8+ T cells primed by antigen-presenting dendritic cells represent the key cell subset in most immunotherapy trials in HCC that have demonstrated positive influence on patient survival [7, 8]. This study investigated effects of local B-cell infiltration in HCC cohorts on patient survival and immunological and molecular tumor microenvironment
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