Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) are becoming the standard of care for recurrent and metastatic cancer. Opioids, the primary treatment for cancer-related pain, are immunosuppressive raising concerns about their potential to interfere with the efficacy of ICIs. We hypothesize that exogenous opioids given for analgesia suppress antitumor immunity via T cell-mediated mu opioid receptor 1 (OPRM1) signaling. METHODS: In silico bioinformatics were used to assess OPRM1 receptor expression on tumor-infiltrating immune cells in patients with head and neck squamous cell carcinoma (HNSCC) and across different cancer types. A syngeneic orthotopic mouse model of oral squamous cell carcinoma was used to study the impact of morphine and OPRM1 antagonism on tumor-infiltrating immune cells, tumor growth and antitumor efficacy of anti-Programmed cell death protein 1 (PD-1) monoclonal antibody treatment. RESULTS: In patients with HNSCC, OPRM1 expression was most abundant in CD8+ T cells, particularly in patients who had not been prescribed opioids prior to resection and exhibited increased expression of exhaustion markers. Exogenous morphine treatment in tumor-bearing mice reduced CD4+ and CD8+ T-cell infiltration and subsequently anti-PD1 ICI efficacy. Peripherally acting mu opioid receptor antagonism, when administered in the adjunctive setting, was able to block morphine-induced immunosuppression and recover the antitumor efficacy of anti-PD1. CONCLUSIONS: These findings suggest that morphine acts via a peripheral OPRM1-mediated mechanism to suppress CD8+ T cells, thereby fostering a pro-tumor-impaired immune response. Importantly, peripherally-restricted OPRM1 antagonism can effectively block this morphine-induced immunosuppression while still allowing for centrally-mediated analgesia, indicating a potential therapeutic strategy for mitigating the adverse effects of opioid pain relief in cancer treatment.