Abstract SY31-02: Nociceptor neurons control anti-tumor immunity

Abstract

Abstract Cancer is the top cause of death in the USA, responsible for 30% of deaths. A cure remains undiscovered. Therapy effectiveness varies by patient and tumor type and can have negative side effects. The immune system, designed to eliminate abnormal cells, including cancer cells, is often impaired. For example, in skin cancer, extended activation of certain receptors can exhaust immune cells, reducing their cancer-fighting ability. Our lab found that cancer cells trigger nociceptor neurons in tumors, leading to neuropeptide release that exhausts CD8+ T cells. To explore their interactions, we conducted single-cell RNA sequencing on tumor-related sensory neurons, leukocytes, and cancer cells. We found a distinct group of tumor-related neurons expressingATF3, Sox10, Sprr1a, and galanin. In our study, mice with injury-resistant nociceptor neurons (NaV1.8ΔATF3) developed smaller melanoma tumors and had reduced galanin levels compared to controls. These mice also showed stronger anti-tumor immune responses, especially in cytotoxic CD8+ T-cells. Restoring galanin in mice with ATF3-deficient nociceptor neurons resulted in tumor growth similar to normal mice. We observed that galanin increases exhaustion, reduces the cytotoxic capacity of CD8+ T-cells, and leads the cells to a state of immunoparalysis. Higher galanin levels in melanoma patients were linked to worse outcomes. Using single-cell RNA sequencing from melanoma patients, we also found that cytotoxic CD8+ T cells with the galanin receptor 1(GALR1) were more exhausted than those without it. In summary, ATF3-modifiedtumor-related sensory neurons that release galanin can weaken anti-tumor immunity, suggesting cancer cells may use this aspect of neuro-immunity to promote tumor growth. Citation Format: Tuany Eichwald, Mohammad Balood, Maryam Ahmadi, Karine Roversi, Dylan Wong, Judith Mandl, Moutih Rafei, Nader Ghasemlou, Paola Vermeer, Moran Amit, Sébastien Talbot. Nociceptor neurons control anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY31-02.