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

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