New Study Discovers Unexpected Reason for Resistance to Cancer Immunotherapy

A joint team of researchers from the University of Texas MD Anderson Cancer Center, the Karolinska Institutet, and Moffitt Cancer Center has discovered an unexpected mechanism behind resistance to cancer immunotherapy: cancer-induced damage to adjacent nerves. 

Immunotherapy is a revolutionary cancer treatment that uses the body’s immune system to fight cancer, thereby avoiding the side effects associated with chemotherapy and radiation. However, over half of cancer patients do not respond to immunotherapy, which has an average success rate of 20-50% across all cancer types. The research team says one reason for this resistance is cancer’s inherent ability to damage nerve cells adjacent to the tumor. 

The study found that cancer cell infiltration causes injury to nerves close to the tumor, causing inflammation that ultimately erodes anti-PD-1 immunotherapy efficacy. This treatment cancels out a mechanism that cancer cells use to avoid destruction by the immune system, allowing the body’s natural defense systems to detect and destroy cancer cells. 

According to the study, nerve injury caused by cancer cell infiltration is directly responsible for reduced immunotherapy efficacy by creating an immune environment that allows tumorous cells to elude treatment. But this process can be reversed, researchers say, opening the door to therapies that can potentially increase immunotherapy effectiveness. 

Analysis of samples from patients in neoadjuvant therapy trials and preclinical models of melanoma, cutaneous squamous cell carcinoma, pancreatic cancer, and gastric cancer showed that cancer cells damage the myelin sheaths of adjacent nerve cells. 

The myelin sheath is a fatty layer that wraps around nerve fibers and insulates them from electrical signal leak, injury, and damage. Once they are damaged, nearby neurons release inflammatory signals such as type 1 interferons which, if not addressed, can cultivate a persistently immunosuppressive tumor microenvironment. 

The team successfully overcame this resistance to anti-PD-1 therapy by directly targeting the cycle through several methods: severing pain-signaling nerves, inhibiting crucial neuronal injury signals, or adding IL-6 pathway blockers to the anti-PD-1 regimen. Co-corresponding study author Kenneth Tsai says the findings show that the nervous system has a clear role in cancer progression and immunotherapy resistance. 

Targeting the inflammatory signaling that occurs after cancer-associated nerve injury allowed his team to re-establish the body’s natural cancer-fighting abilities, he says. The breakthrough represents a significant shift in our understanding of cancer immunotherapy resistance, and it could lead to new treatment combinations that improve outcomes for thousands of cancer patients who wouldn’t have responded to immunotherapy treatments. 

As more firms like Calidi Biotherapeutics Inc. (NYSE American: CLDI) continue their efforts to develop more effective immunotherapies, a lot more is likely to be uncovered about the different mechanisms that cancer uses to evade the immune system or become resistant to existing therapies. 

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