GITR Engagement on ILC2s Drives IL-9 Production, Recruiting Eosinophils to Suppress Tumor Growth

Innate lymphoid cells (ILCs) are crucial regulators of tissue immunity, yet their specific roles in tumor control remain underexplored. While adaptive immunity is a focus of cancer immunotherapy, the contribution of innate lymphocytes, particularly group 2 ILCs (ILC2s), to the tumor microenvironment and anti-tumor responses is increasingly recognized. Understanding how ILC2s can be leveraged to promote innate anti-tumor immunity could offer novel therapeutic avenues, especially in cases where adaptive immune responses are insufficient or suppressed.

Researchers combined analyses of human sequencing datasets with genetic ablation mouse models and adoptive transfer experiments. They investigated the impact of glucocorticoid-induced tumor necrosis factor receptor (GITR) engagement on tumor-infiltrating ILC2s. The study assessed IL-9, IL-5, and IL-13 production, intratumoral eosinophil accumulation, survival, tissue retention, and cytotoxicity. Eosinophil ablation and adoptive transfer experiments were used to confirm their role in GITR-mediated tumor control, with tumor growth as a primary endpoint.

Engagement of GITR on tumor-infiltrating ILC2s induced activating transcription factor 3 (ATF3) and robust interleukin-9 (IL-9) production, which significantly exceeded the modest co-induction of IL-5 and IL-13. ILC2-derived IL-9 promoted intratumoral eosinophil accumulation by enhancing their survival, tissue retention, and cytotoxicity through tumor-induced IL-9 receptor expression. > Eosinophil ablation completely abolished GITR-mediated tumor control, whereas adoptive eosinophil transfer successfully restored it, highlighting their indispensable role. This IL-9-eosinophil pathway effectively suppressed tumor growth even in the absence of adaptive lymphocytes. In human datasets, IL-9 and eosinophil signatures were consistently associated with a favorable prognosis in both melanoma and lung adenocarcinoma.