Researchers have uncovered that cancer cells degrade protective nerve coverings, causing cancer-induced nerve injury that can lead to chronic inflammation and resistance to anti–PD-1 immunotherapy, according to findings published in Nature.
In exploring the role of perineural invasion and cancer-associated nerve injury in relation to immunotherapy resistance in patients with cutaneous squamous cell carcinoma, melanoma, and gastric cancer, the researchers found that targeting the same pathway involved in the cancer-induced nerve injury at different points may mitigate immunotherapy resistance and improve responses to PD-1 inhibition.
“These findings uncover novel mechanisms by which the immune system and nerves within the tumor microenvironment interact, revealing actionable targets that could transform the way we approach resistance to immunotherapy in patients with cancer,” stated co-corresponding study author Moran Amit, MD, PhD, Professor of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center. “This marks a significant advance in our understanding of tumor-neuro-immune dynamics, highlighting the importance of investigating the interplay of cancer and neuroscience in meaningful ways that can directly impact clinical practice.”
Study Methods and Findings
The study authors wanted to explore more of the immunoregulatory role of cancer-induced nerve injury and perineural invasion, which leads to poor prognosis across several cancer types. They conducted a neuroscience study of clinical and mechanistic interactions between cancer and the nervous system, analyzing trial samples using advanced genetic, bioinformatic, and spatial techniques, looking especially at patients with cutaneous squamous cell carcinoma, melanoma, and gastric cancer.
Through electron microscopy and electrical conduction analyses, they found that cancer cells can degrade the nerve fibre myelin sheets, which causes the injured neurons to autonomously initiate IL-6 and type I interferon-mediated inflammation to promote nerve healing and regeneration. The burden of the nerve injury increases in line with the tumor's growth, however, making the inflammation chronic and the immune system become exhaustive and suppressive, leading to resistance to anti–PD-1 immunotherapy.
The study authors found that the resistance could be reversed by targeting multiple steps in the cancer-induced nerve injury signaling process, including denervating the tumor, conditional knockout of the transcription factor mediating the injury signal within neurons, knockout of interferon-α receptor signaling, and through the combination of anti–PD-1 and anti–IL-6-receptor blockade.
Disclosure: The study was funded in part by the James P. Allison Institute and the Cancer Neuroscience Program at MD Anderson. For full disclosures of the study authors, visit nature.com.
