Cancer-Induced Nerve Injury—A New Frontier in Overcoming Anti-PD-1 Resistance

A recent study published in Nature investigated new ways that cancer can make people resistant to anti-PD-1 therapy. It found that cancer-induced nerve injury (CINI) and perineural invasion (PNI) are two direct immunoregulatory mechanisms that make people resistant to the therapy in a number of cancer types, such as gastric cancer, cutaneous squamous cell carcinoma (cSCC) and melanoma.

The introduction of anti-PD-1 and PD-L1 immunotherapies has changed oncology forever, yet there is still a big problem: most patients still don't respond to treatment. Historically, the exact way that PNI leads to bad outcomes and its involvement in controlling the immune system in the tumor microenvironment (TME) has not been well understood. PNI is also a well-known sign of a bad prognosis in many forms of cancer. This study offers both clinical and molecular insights into its function in resistance to anti-PD-1 treatment.

Erez Baruch, M.D., PhD., from the Division of Cancer Medicine, Hematology and Oncology Fellowship program at The University of Texas MD Anderson Cancer Center in Houston, TX, and his team used numerous methods, including clinical, in vivo, and in vitro, to figure out how this complicated interaction works. The researchers performed comprehensive investigations, encompassing multiomics analysis of human patient cohorts with diverse PNI-associated malignancies, in vitro studies utilizing mouse and human neurons, and in vivo models employing genetically modified mice.

Tumor samples from clinical cohorts of patients with cSCC, melanoma, and gastric cancer receiving anti-PD-1 therapy were studied. Techniques included multiplex immunofluorescence to look for nerve injury indicators like ATF3 and JUN, bulk RNA sequencing to find gene expression patterns of PNI/nerve injury, and digital spatial profiling and spatial transcriptomics to see where immune activity is happening in neural niches.

Different animal models (cSCC, melanoma) were employed to functionally confirm the role of nerves. The experiments included tumor denervation (nerve removal), surgical axotomy (nerve severing) and genetically engineered mice with conditional knockouts of important signaling molecules (Atf3-cKO, Ifnar1-KO). These models enabled researchers to evaluate the effects of nerve injury and targeted therapies on tumor proliferation and anti-PD-1 response.

Co-cultures comprising human and murine cancer cells alongside dorsal root ganglion and trigeminal ganglia neurons were created. Researchers also used electron microscopy to see how the structure of nerves changed, as well as electrical conduction investigations and Luminex immunoassays to see how active the nerves were and how much cytokine they were secreting.

The principal findings clearly illustrated the immunoregulatory function of CINI. PNI and CINI were significantly correlated with suboptimal responses to anti-PD-1 therapy across various cancer types. People who didn't respond had higher amounts of neuronal injury indicators, such as ATF3, which is a transcription factor that mediates the injury signal. Cancer cells also directly damage nerves by breaking down the myelin sheaths that protect nerve fibers, which makes it harder for electrical signals to travel.

Damaged neurons independently trigger an inflammatory response marked by the secretion of IL-6 and type I interferon, facilitating nerve repair and regeneration. As CINI advances, this nerve-driven inflammation becomes chronic, causing the immune response to become suppressive and fatigued, which brings in immunosuppressive macrophages and fatigued CD8+ T cells.

The findings show that CINI-induced anti-PD-1 resistance is reversible. Strategies such as tumor denervation, conditional knockout of the injury-mediating transcription factor Atf3 in neurons, knockout of Ifnar1 (interferon-α receptor signaling), or combining anti-PD-1 with anti-IL-6 receptor blockade greatly improved the effectiveness of anti-PD-1 and lowered immunosuppression.

These results have significant ramifications for anti-PD-1 treatment. They demonstrate that CINI functions not only as a prognostic indicator but also as a direct immunoregulatory mechanism that facilitates resistance to checkpoint blockage. This understanding paves the way for novel treatment interventions. Targeting the neuronal damage signal (e.g., Atf3) or downstream inflammatory mediators such as IFN-I and IL-6 may provide innovative approaches to surmount resistance and enhance patient outcomes.

Moreover, these insights may facilitate the discovery of novel biomarkers that forecast response to anti-PD-1 therapy and inform the formulation of combination therapies. The medical community may be able to use immunotherapy to its full capacity for more cancer patients if they deal with CINI.