Reciprocal regulation of neutrophils and B cells elicits autoantibody-associated protumorigenic effects in human hepatocellular carcinoma

Abstract

Abstract Despite recent advances in identifying autoantibody-mediated carcinogenesis in animal models, direct evidence supporting the important role of autoantibodies in the immunopathogenesis of human cancers is still lacking. We recently found that neutrophils are accumulated in hepatocellular carcinoma (HCC), and their levels positively correlated with poor survival of patients. Here we detected high titers of proteinase 3 (PR3)-specific anti-neutrophil cytoplasmic autoantibodies (ANCA) in plasma from patients with advanced stage HCCs, and that increased titers of anti-PR3 autoantibodies also correlated with poor clinical outcome of patients. Neutrophils, B cells, plasma cells all predominantly accumulated in the peritumoral stroma of HCC tumors. The neutrophils isolated from HCC tumors, but not paired blood, significantly and effectively secreted PR3 proteins; accordingly, only B cells/plasma cells derived from HCC tumors markedly produced anti-PR3 autoantibodies. Further kinetic experiments revealed addition of conditioned medium from HCC tumor neutrophils to the ex vivo induction system of plasma cells led to sequential B cell activation, somatic hypermutation, and anti-PR3 autoantibody secretion. Reciprocally, we also demonstrated that, in the presence of anti-PR3 autoantibodies, the neutrophils are more potent to produce protumorigenic factors oncostatin M and matrix metalloproteinase-9. Thus, the secretion of PR3 by tumor neutrophils may represent a novel mechanism that links the autoimmunity to disease progression in the tumor milieu.