Oncogenic mutations drive immunity through a neuron-ILC axis 2307494

Abstract Introduction The tumor microenvironment (TME) in established cancers is well studied due to its critical role in patient response to immunotherapy. However, much less is known about how the TME and immune recognition evolve during the earliest stages of tumor initiation. We investigated how oncogenic mutations in tissue-resident stem cells shape early immune responses in the skin before visible tumor formation. Methods We used complementary molecular, cellular, and imaging approaches, including single-cell RNA sequencing, flow cytometry, and immunofluorescence, to characterize early immune responses in skin harboring oncogenic mutations in tissue-resident stem cells. These methods were used to define immune cell composition, activation states, and interactions within the evolving tissue microenvironment. Results Oncogenic mutations in epidermal stem cells triggered a strong early immune infiltration prior to the appearance of any cancerous lesion. This response consisted predominantly of locally proliferating ILC1s. ILC1s in mutated skin expressed elevated levels of Granzyme C and the activation receptor NKp46, consistent with their rapid response capacity and involvement in anti-tumor immunity. Mutated stem cells upregulated the neuropeptide PYY, whose receptor is present on skin-innervating neurons. Loss of PYY in mutated skin correlated with reduced ILC1 numbers, suggesting that neuronal signaling downstream of stem-cell-derived PYY promotes activation and expansion of dermal ILC1s. Conclusion Mutations in otherwise healthy-appearing stem cells are sufficient to reshape the tissue microenvironment. Our findings identify a stem cell—neuron—ILC1 axis that primes early immune surveillance and contributes to controlling tumor formation during the initial stages of carcinogenesis. Funding Source NYSCF Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)