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bioRxiv · 10.64898/2026.04.28.721482

Circulating inflammatory ILC2s as a biomarker of gastric cancer progression

O'Keefe, R. N.·Raghunathan, K.·Eissmann, M. F.·Baloyan, D.·Poh, A. R.·O'Brien, M.·Clapdorp, E.·Afshar-Sterle, S.·Locksley, R. M.·Ernst, M.·Buchert, M.
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Abstract

Gastric cancer is frequently diagnosed at an advanced stage, contributing to poor patient outcomes and highlighting the need for blood-based biomarkers that can detect disease earlier and track progression. We previously showed that a tuft cell-IL25-type 2 innate lymphoid cell (ILC2) circuit promotes gastric metaplasia and gastric tumour development, but whether this pathway gives rise to a circulating ILC2 population remained unknown. Here, we show that IL25-responsive inflammatory ILC2s (iILC2s) emerge in the blood across gastric disease progression and are selectively associated with gastric tumour contexts. Using multiple mouse models spanning SPEM, early gastric adenoma, and advanced gastric cancer, we found that circulating ILC2s increased progressively with disease severity, with the dominant increase occurring in the IL17RB+ iILC2 subset. This response was not observed in pancreatic or ovarian tumour models, indicating that circulating iILC2 mobilisation is not a general consequence of tumour burden. Instead, mobilisation was linked to gastric disease and accompanied by increased ILC2 accumulation in distal mucosal tissues. Genetic tuft cell ablation or therapeutic blockade of IL25 or IL13 significantly reduced circulating iILC2s, demonstrating that this response depends on the tuft cell-IL25 circuit. In vivo, mobilised iILC2s were associated with enhanced growth of distal tumour implants, supporting a functional contribution beyond the primary gastric site. Translationally, circulating ILC2s were elevated in patients with gastric inflammatory disease and gastric cancer, with the IL25-responsive subset predominating. Circulating ILC2s also showed strong discriminatory power between gastric cancer patients and healthy controls in ROC analysis, supporting their potential utility as a blood-based biomarker. Together, these findings identify circulating iILC2s as a systemic hallmark of gastric tuft cell-ILC2 signalling and establish their mechanistic and translational relevance in gastric cancer.

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O'Keefe, R. N., Raghunathan, K., Eissmann, M. F., Baloyan, D., Poh, A. R., O'Brien, M., Clapdorp, E., Afshar-Sterle, S., Locksley, R. M., Ernst, M., Buchert, M.. 2026-05-01. Circulating inflammatory ILC2s as a biomarker of gastric cancer progression. https://doi.org/10.64898/2026.04.28.721482

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