Opioids, commonly used for cancer-related pain management, can hinder the effectiveness of immunotherapy. Research from the University of Pittsburgh and UPMC Hillman Cancer Center reveals that peripherally restricted OPRM1 antagonists (PAMORAs) can counteract opioid-induced immunosuppression, thereby enhancing the response to immune checkpoint inhibitor therapy. The study, published in the Journal for ImmunoTherapy of Cancer, highlights the potential of PAMORAs to maintain pain relief while enabling the immune system to combat cancer more effectively.
Opioids and Immunosuppression
"It is imperative – especially in head and neck cancer, which is one of the most painful cancers – that patients are comfortable during treatment," said Dr. Nicole Scheff, assistant professor at Pitt School of Medicine and UPMC Hillman. However, their research indicates that opioids like morphine can limit the ability of immune checkpoint inhibitors to reactivate the tumor-associated immune response. In a mouse model of oral cancer, morphine suppressed the response to anti-PD1 immune checkpoint therapy, resulting in fewer cancer-killing CD8 T cells, larger tumors, and reduced survival rates.
Mechanism of Action
Analyzing samples from both mice and patients with head and neck cancer, the researchers discovered that morphine binds to the OPRM1 receptor on CD8 T cells, suppressing their activity and negating the effects of anti-PD1 therapy. This interaction provides a mechanistic explanation for why some patients do not respond to immune checkpoint inhibitors, despite appearing to be good candidates for such treatment.
Potential Therapeutic Strategy
According to Scheff, immune checkpoint therapies are becoming standard care for recurrent and metastatic cancer, but response rates are less than 20% in head and neck cancer. The study suggests that limiting opioid prescriptions prior to immunotherapy could improve response rates. In cases where severe pain necessitates opioid use, PAMORAs may offer a solution by preserving analgesia while allowing the immune system to function effectively.
PAMORAs: A Promising Solution
PAMORAs, such as methylnaltrexone (approved for opioid-induced constipation) and axelopran (in development), block the effects of opioids in the body without crossing the blood-brain barrier, thus preserving their pain-relieving properties. When administered with morphine, methylnaltrexone and axelopran almost completely blocked opioid-induced immunosuppression in mice, allowing anti-PD1 therapy to be effective.
Future Directions
The researchers are now investigating how other opioid derivatives that act on the OPRM1 receptor, such as buprenorphine, affect the immune system, aiming to further refine strategies for combining pain management with effective cancer immunotherapy.
