Inhibition of adaptive immunity by IL-9 can be disrupted to achieve rapid T cell sensitization and rejection of progressive tumor challenges.

The tolerogenic cytokine IL-9 promotes T regulatory cell function and allergic airway inflammation, but it has not been extensively studied in cancer. In this report, we employed IL-9 deficient mice to investigate the effects of IL-9 in multiple models of breast and colon cancer development. Eliminating endogenous IL-9 enabled sensitization of host T cells to tumors, leading to their early rejection without the requirement of vaccines or immunomodulatory therapies. Notably, IL-9-deficient mice acquired immunologic memory, which actively protected from residual disease and tumor rechallenge, an effect linked to activation of CD8+ T cells. Depletion of either CD8+ or CD4+ T cells abolished the benefits of IL-9 loss to tumor control. Adoptive transfer experiments showed that T cells from tumor-rejecting IL-9-deficient mice retained their effector competency in wild-type animals. Moreover, neutralizing IL-9 antibody phenocopied the effects of IL-9 gene deletion by slowing tumor progression in wild-type animals. Our results show the ability of IL-9 to function as an inhibitor of adaptive immunity that prevents the formation of immunologic memory to a growing tumor, highlighting the potential for IL-9 neutralization as a unique tool for cancer immunotherapy.