{"doi":"10.1136/jitc-2024-009962","title":"Morphine treatment restricts response to immunotherapy in oral squamous cell carcinoma","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.","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":426255,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1225133,"name":"Andre A Martel Matos","orcid":"0000-0003-0297-9622","position":1,"is_corresponding":false},{"id":876959,"name":"Mona Yuan","orcid":null,"position":2,"is_corresponding":false},{"id":876428,"name":"Megan A. Atherton","orcid":"0000-0001-6199-4131","position":3,"is_corresponding":false},{"id":1225720,"name":"Fendi Obuekwe","orcid":null,"position":4,"is_corresponding":false},{"id":557790,"name":"Marci L. Nilsen","orcid":"0000-0002-5888-668X","position":5,"is_corresponding":false},{"id":1225134,"name":"Amin Reza Nikpoor","orcid":"0000-0001-5619-8771","position":6,"is_corresponding":false},{"id":557359,"name":"Sébastien Talbot","orcid":"0000-0001-9932-7174","position":7,"is_corresponding":false},{"id":109276,"name":"Tullia C. Bruno","orcid":"0000-0002-6433-0207","position":8,"is_corresponding":false},{"id":1225721,"name":"David N Taggart","orcid":null,"position":9,"is_corresponding":false},{"id":1225722,"name":"Lorin K Johnson","orcid":null,"position":10,"is_corresponding":false},{"id":109277,"name":"Robert L. Ferris","orcid":"0000-0001-6605-2071","position":11,"is_corresponding":false},{"id":477535,"name":"Dan P. Zandberg","orcid":"0000-0002-1002-8301","position":12,"is_corresponding":false},{"id":347878,"name":"Nicole N. Scheff","orcid":"0000-0002-5587-4990","position":13,"is_corresponding":false},{"id":876427,"name":"Lisa A. McIlvried","orcid":"0000-0002-2030-1316","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T01:58:37.924718Z","pmid":"39551606","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}