The E3 Ubiquitin Ligase Asb2α in T Helper 2 Cells Negatively Regulates Antitumor Immunity in Colorectal Cancer

Abstract

The escape of cancer cells from host immunosurveillance involves a shift in immune responses, including an imbalance in Th1 and Th2 cells. A Th1-dominated immune response predicts positive outcomes in colorectal cancer. The E3 ubiquitin ligase, Asb2α, is expressed in Th2 cells, but its roles in T-cell maturation and cancer are unclear. We provide evidence that the Th2 master regulator, Gata3, induces <i>Asb2</i> Loss of <i>Asb2</i> did not affect Th differentiation <i>ex vivo</i>, but reduced IL4 production from Th2 cells. We found that high <i>ASB2</i> expression was associated with poor outcome in colorectal cancer. Loss of <i>Asb2</i> from hematopoietic cells promoted a Th1 response and attenuated colitis-associated tumorigenesis in mice. Diminished Th2 function correlated with increased IFNγ production and an enhanced type 1 antitumor immune response in <i>Asb2</i>-deficient mice. Our work suggests that Asb2α promotes a Th2 phenotype <i>in vivo</i>, which in turn is associated with tumor progression in a mouse model of colitis.