Background & Aims
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. We aimed to investigate the impact of ATF3-deficient nociceptor neurons on melanoma tumor and anti-tumor immunity, and explore the role of the neuropeptide galanin in immune exhaustion and tumor growth.
Methods
We performed single-cell RNA sequencing on tumor-associated sensory neurons, leukocytes, and cancer cells to elucidate their interplay. Additionally, we generated mice with injury-resistant nociceptor neurons (NaV1.8?ATF3) to evaluate the impact of galanin restoration on tumor growth and immune exhaustion in these animals. Subsequently, we conducted in silico analysis using single-cell RNA sequencing data from melanoma patients to validate the correlation between galanin receptor expression and patient survival.
Results
We found a distinct group of tumor-related neurons expressing ATF3, Sox10, Sprr1a, and galanin. In our study, mice with injury-resistant nociceptor neurons (NaV1.8?ATF3) 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.
Conclusions
In summary, ATF3-modified tumor-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.
References
Balood, M. et al. Nociceptor neurons affect cancer immunosurveillance. Nature 611, 405–412 (2022).
Restaino, A. C. et al. Functional neuronal circuits promote disease progression in cancer. Sci. Adv. 9, eade4443 (2023).
Amit, M., Na’ara, S. & Gil, Z. Mechanisms of cancer dissemination along nerves. Nat. Rev. Cancer 16, 399–408 (2016).
Ali, S. R., Jordan, M., Nagarajan, P. & Amit, M. Nerve Density and Neuronal Biomarkers in Cancer. Cancers (Basel). 14, (2022).
Presenting Author
Tuany Eichwald
Poster Authors
Tuany Eichwald
PhD
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Lead Author
Mohammad Balood
PhD
Department of Pharmacology and Physiology, University of Montreal, Montreal, Canada
Lead Author
Maryam Ahmadi
PhD
Department of Pharmacology and Physiology, University of Montreal, Montreal, Canada;
Lead Author
Karine Roversi
PhD
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada
Lead Author
Amin Reza Nikpoor
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada
Lead Author
Ali Ahmadi
Department of Pharmacology and Physiology, University of Montreal, Montreal, Canada
Lead Author
Dylan Wong
PhD
Department of Physiology, McGill University, Montreal, Canada
Lead Author
Judith Mandl
PhD
Department of Physiology, McGill University, Montreal, Canada
Lead Author
Moutih Rafei
PhD
Department of Pharmacology and Physiology, University of Montreal, Montreal, Canada
Lead Author
Paola Vermeer
PhD
Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, USA
Lead Author
Moran Amit
PhD
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
Lead Author
Sebastien Talbot
PhD
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Lead Author
Topics
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