Background

Gastric cancer (GC) is the 3^rd leading cause of cancer-related mortality worldwide with a predicted increase of 40% over the next two decades¹, on top of the current one million new cases annually and close to 900,000 deaths², thereby emphasising the need for greater understanding of molecular drivers of the disease.

Tuft cells and ILC2s

Currently the function of tuft cells, a rare population of chemo-sensory epithelial cells that line the gastrointestinal and respiratory tracts, is uncertain. Tuft cells have previously being identified as a quiescent stem cell³, while other studies have found tuft cells to rarely proliferate⁴. Additionally, in response to helminth infections and other external stimuli, tuft cells secrete cytokines (e.g. interleukin (IL) 25), inflammatory mediators (e.g. eicosanoids), neurotransmitters (e.g. acetylcholine), and other signaling molecules to promote immune cell activation and restore tissue homeostasis^5-9. Emerging evidence suggests that tuft cells may also orchestrate early oncogenic processes, as suggested by their rapid expansion and cancer stem cell-like properties observed in pre-neoplastic lesions of the gastrointestinal tract^10,11. Within gastrointestinal tissues, tuft cell derived IL25 promotes the activation of type 2 innate lymphoid cells (ILC2s), and their subsequent production of IL13 stimulates the expansion of tuft cells^8,12.

Tuft cells and ILC2s in gastric disease

Although ILC2s are best understood for their contribution to immune defense against intestinal parasites, they are increasingly recognized as a novel immune cell type regulating anti-tumor immune responses^13-17. Moreover, ILC2s have been linked to Helicobacter pylori driven gastric metaplasia in humans and mice¹³, as well as a source of IL13 during chemically induced metaplasia, with depletion of ILC2s resulting in reduced tuft cell hyperplasia and gastric metaplasia¹⁸.

While ILC2s have been found to be increased in the blood of gastric cancer patients¹⁹, however it remains unclear whether these cells contribute to the initiation and progression of GC. Here, we provide complementing evidence that a cytokine-supported tuft cell-ILC2 circuit, optimized to combat intestinal helminth infection, becomes coerced to underpin gastric metaplasia and cancer in mice, and remains evident as a therapeutic vulnerability in human GC.

Our findings

In our study we found that the tuft cell-ILC2 feed-forward circuit provides another facet of a wound-healing mechanism being hijacked to promote progression of neoplastic transformed cells. This occurs at the early metaplastic, adenomatous and later carcinoma stages and includes cytokine-dependent regulatory circuits that couple with local arising inflammatory triggers with an ensuing epithelial response. This tuft cell-ILC2 circuit is maintained by complementary IL25 and IL13 signaling between the two cell types arranged as non-redundant “single-point of failure” mechanisms. Through our experiments we found that genetic interference of the circuit through ablation of either tuft cells or ILC2s, or therapeutic suppression of IL13 or IL25 signaling, confers therapeutic benefits at both earliest stages (i.e. gastric metaplasia) as well as later stages (i.e. gastric adenomas and adenocarcinomas) along the tumor trajectory.

Final word

We predict that the functional insights from our preclinical models will be relevant to human GC, as tuft cell and ILC2 expression signatures were associated with poorer survival in patients with intestinal-type GC. A swift clinical translation of our discovery is supported by the availability of α-IL13 monoclonal antibodies that are currently optimized for the treatment of severe asthma²⁰ and the prospect of developing companion diagnostics for early detection of GC and patient stratification.

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