Department of Otorhinolaryngology-Head and Neck Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
Biomolecules. 2023 Nov 22;13(12):1685. doi: 10.3390/biom13121685.
Although anti-programmed death-1 (PD-1) antibody therapy improves the prognosis in patients with head and neck squamous cell carcinoma (HNSCC), some patients exhibit disease progression even after showing a good response to the treatment initially because of acquired resistance. Here, we aimed to reveal the dynamic changes in the tumor and tumor microenvironment (TME) in a 77-year-old man diagnosed with oral squamous cell carcinoma who developed acquired resistance after the administration of nivolumab using spatial transcriptomics. The results showed that, before immunotherapy, the activated pathways in the tumor area were mainly related to the cancer immune system, including antigen processing cross-presentation, interferon-gamma signaling, and the innate immune system. After immunotherapy, the activated pathways were mainly related to epigenetic modification, including RMTs methylate histone arginine and HDAC deacetylates histones. Before immunotherapy, the activated pathways in the TME were mainly related to the metabolism of proteins, including SRP-dependent co-translational protein targeting the membrane. After immunotherapy, the activated pathways in the TME were related to sensory perception and signal transduction. Our study revealed that epigenetic-modification-related pathways were mainly activated after establishing acquired resistance, suggesting that epigenetic modification in the tumor may prevent cancer immune system activation via the anti-PD-1 antibody.
尽管抗程序性死亡-1（PD-1）抗体疗法改善了头颈部鳞状细胞癌（HNSCC）患者的预后，但一些患者在最初对治疗有良好反应后仍出现疾病进展，这是因为产生了获得性耐药。在这里，我们旨在使用空间转录组学揭示一名 77 岁男性口腔鳞状细胞癌患者在接受 nivolumab 治疗后发生获得性耐药时肿瘤和肿瘤微环境（TME）的动态变化。结果表明，在免疫治疗之前，肿瘤区域中激活的途径主要与癌症免疫系统有关，包括抗原加工交叉呈递、干扰素-γ信号和固有免疫系统。免疫治疗后，激活的途径主要与表观遗传修饰有关，包括 RMTs 甲基化组蛋白精氨酸和 HDAC 去乙酰化组蛋白。免疫治疗前，TME 中激活的途径主要与蛋白质代谢有关，包括 SRP 依赖性共翻译蛋白靶向膜。免疫治疗后，TME 中激活的途径与感觉感知和信号转导有关。我们的研究表明，获得性耐药后主要激活了与表观遗传修饰相关的途径，这表明肿瘤中的表观遗传修饰可能通过抗 PD-1 抗体阻止癌症免疫系统的激活。
