巨噬细胞Nrf2通路对肿瘤免疫治疗中免疫相关副作用（irAE）的调控及机制

免疫相关副作用（irAE）是肿瘤免疫检查点抑制剂（ICIs）治疗过程中独特的副作用，整体发生几率高，严重的irAE（包括免疫性肠炎、免疫性肝炎、免疫性肺炎等）可致死。目前关于irAE的发生机制尚不明确。易发生irAE的器官含有大量组织驻留巨噬细胞（TRM），且部分TRM表达PD-1/PD-L1，因此ICIs不可避免的会对TRM产生影响，提示TRM可能与irAE密切相关。前期研究中，申请人构建了肿瘤免疫治疗模型。通过转录组分析发现TRM的关键保护信号Nrf2在anti-PD1治疗后明显降解。基于此，本课题将深入研究TRM中Nrf2信号通路对irAE的重要调节作用，揭示anti-PD1/PD-L1调控Nrf2通路的分子机制，大规模临床样本分析Nrf2信号通路与irAE的相关性，并检测激活Nrf2信号通路的潜在疗效，为靶向TRM中Nrf2信号通路控制irAE进而提高免疫治疗的安全性提供理论基础。

Immune checkpoint inhibitors (ICIs) targeting CTLA-4) and PD-1/PD-L1 have shown remarkable antitumor activity in an increasing number of cancers. Responses occur in a substantial fraction of patients (about 20%, cancer type dependent) and are frequently durable and even curative. By unbalancing the immune system, these ICIs also generate specific toxicities, called immune-related adverse events (irAE) that mainly involve the gut, skin, endocrine glands, liver, and lung. Anti-CTLA-4 triggers substantially more irAE than anti-PD1/PD-L1 (55%-60% vs 10%-20% high-grade events). These toxic effects remain a major challenge in clinical care..Macrophages are myeloid lineage hematopoietic cells that are specialized in phagocytosis. Tissue-resident macrophages (TRM, including microglia in brain, Kupffer cells in liver, splenic red pulp macrophages in spleen, and alveolar macrophages in lung) play important homeostatic roles, depending on the tissue in which they reside. ICIs mainly target CTLs and tumor cells. However, as many TRM also expressing PD-1/PD-L1, TRM are unavoidably affected by ICIs, providing a potential link between TRM and irAE..In this study, we constructed a mouse immunotherapy to study the mechanisms of irAE. By analyzing the transcriptome dynamics of lung TRM during anti-PD1 therapy, we found Nrf2 signaling pathway is significantly inhibited, possibly by ubiquitination degradation. Nrf2 signaling pathway plays a vital role in anti-inflammation, anti-oxidase, and cell protection. Our following study will focus on how TRM Nrf2 signaling was affected by anti-PD1/PD-L1. Combine with animal model and clinical data analysis, this study will elucidate the molecular mechanism responsible for TRM Nrf2 inhibition by anti-PD1/PD-L1 and inducing tissue damage, thus providing a promising therapeutic target in the treatment of irAE during ICIs therapy.