Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Immunother Cancer. 2024 Nov 17;12(11):e009962. doi: 10.1136/jitc-2024-009962.
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.
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.
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.
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.
免疫检查点抑制剂（ICIs）正在成为复发性和转移性癌症的标准治疗方法。阿片类药物是治疗癌症相关疼痛的主要药物，但具有免疫抑制作用，这引发了人们对其潜在干扰 ICI 疗效的担忧。我们假设，用于镇痛的外源性阿片类药物通过 T 细胞介导的 μ 型阿片受体 1（OPRM1）信号抑制抗肿瘤免疫。
使用计算机生物信息学评估头颈部鳞状细胞癌（HNSCC）患者和不同癌症类型的肿瘤浸润免疫细胞中 OPRM1 受体的表达。使用口腔鳞状细胞癌的同源原位小鼠模型研究吗啡和 OPRM1 拮抗作用对肿瘤浸润免疫细胞、肿瘤生长和抗 PD-1 单克隆抗体治疗疗效的影响。
在 HNSCC 患者中，OPRM1 表达在 CD8+T 细胞中最为丰富，尤其是在未接受阿片类药物治疗且表现出衰竭标志物表达增加的患者中。荷瘤小鼠给予外源性吗啡治疗可减少 CD4+和 CD8+T 细胞浸润，进而降低抗 PD-1 ICI 疗效。在辅助治疗中给予外周作用的 μ 型阿片受体拮抗剂能够阻断吗啡诱导的免疫抑制并恢复抗 PD-1 的抗肿瘤疗效。
这些发现表明，吗啡通过外周 OPRM1 介导的机制作用于 CD8+T 细胞，从而促进促肿瘤免疫反应受损。重要的是，外周限制的 OPRM1 拮抗剂可以有效地阻断吗啡诱导的免疫抑制，同时仍允许中枢介导的镇痛，这表明了一种潜在的治疗策略，可减轻癌症治疗中阿片类药物缓解疼痛的不良反应。
