Overcoming Immunotherapy Resistance Through Opioid Antagonism in Head and Neck Cancer

PROJECT SUMMARY Current treatment for head and neck squamous cell carcinoma (HNSCC) results in 5-year survival rates around 63%; however, treatment is often associated with significant pain as well as a 50% recurrence rate within the first 2 years. Opioids are the primary strategy for pain control, and the drug requirement is high, with dosages increasing as tolerance develops. The majority of HNSCC patients are prescribed opioids with treatment; persisent opioid use continues during survivorship and in recurrent/metastatic (R/M) HNSCC patients. While providing some pain relief, opioids can be immunosuppressive, which can impede treatment response. Immune checkpoint inhibitors (ICIs) are the current first-line systemic treatment strategy for R/M HNSCC patients, but fewer than 20% of patients respond to therapy. The impact of concomitant use of opioids and ICI is currently unknown. Preliminary data using a study cohort of 66 R/M HNSCC patients who received anti-PD1 monoclonal antibody therapy found that 63% of patients were actively taking opioids for pain prior to treatment. In this cohort, high opioid usage was associated with lower intratumoral CD8+ T cell density in the tumor biopsy tissue prior to treatment and significantly lower overall survival in response to ICI treatment. Additionally, using a syngeneic orthotopic transplant mouse model, the Oprm1 gene was upregulated in tumor infiltrating lymphocytes (TIL), and acute morphine administration reduced the CD8+ TIL frequency by 90% in vivo. Methylnaltrexone (MNTX), a peripheral-acting OPRM1 antagonist, completely blocked the morphine- induced immunosuppression in our mouse model. The hypothesis of this proposal is that exogenous opioids given for analgesia suppress anti-tumor immunity via immune-mediated OPRM1 signaling. To test this hypothesis, we will use preclinical mouse models to investigate the functional impact of OPRM1 signaling in CD8+ T cells on anti-tumor immunity and tumor growth as well as determine the neoadjuvant potential of MNTX to block opioid-induced immunosuppression and improve ICI response. Additionally, we will use single cell RNA sequencing and multispectral imaging on preclinical and human tumor tissue to provide a single-cell level view of anti-tumor immunity with direct consideration of the immunosuppressive effects of opioid usage. We believe this proposal will lead to new strategies to overcome immunotherapy resistance, a critical need for improving outcomes in HNSCC disease.