Project Grant R01DE033473

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.