Inhibition of Adaptive Immunity by IL9 Can Be Disrupted to Achieve Rapid T-cell Sensitization and Rejection of Progressive Tumor Challenges

Abstract

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.

Induction of antigen‐specific TH9 immunity accompanied by mast cell activation blocks tumor cell engraftment

“…The role of T H 9‐derived IL‐9 remains controversial in the context of tumor immunology. Hoelzinger and colleagues suggested that neutralization of IL‐9 helped alleviate tumor burdens while other studies suggested a beneficial (protective) role for IL‐9 against B16 melanoma cells through a multivariate effector response . Importantly, Purwar et al .…”

“…A recent report suggested that the development of T H 9 immunity arises from a failure to mount a T H 17 response . In vitro , the addition of a combination of TGF‐β and IL‐4 can yield IL‐9 producing CD4+ cells by down regulating the DNA‐binding inhibitor Id3, thereby allowing for an enhancement in the binding of the transcription factors E2A and GATA‐3 to the il9 promoter region . A recent study suggested that the stimulation of glucocorticoid‐induced tumor necrosis factor receptor (TNFR)‐related protein (GITR) signaling favors the development of T H 9 cells in vivo .…”

Treating tumors with immune checkpoint inhibitors: Rationale and limitations

“…These results suggest that high TGF-β levels in responders prior to treatment may allow increased induction of Th9 cells upon anti-PD-1 treatment, which in turn may improve cytotoxic anti-tumor immune responses [52] . However, it should be noted that the role of Th9 cells in antitumor immunity is still controversial with various studies suggesting that IL-9 can either promote or inhibit anti-tumor immune responses [53][54][55] .…”

Les lymphocytes Th9

“…Un ralentissement de la croissance tumorale a été observé chez des souris porteuses de tumeurs coliques après vaccination par un lysat de cellules isolées de tumeurs coliques associé à de l'alun. Le développe-ment d'une réponse de type Th2, au sein de la tumeur, [41]. Le rejet des tumeurs chez ces souris est conditionné par la présence de lymphocytes T CD4 et surtout T CD8 dont la déplétion rétablit la progression tumorale.…”