Zheng Linpeng, Lin Fenglin, Cai Dingqin, Zhang Longyao, Yin Chenrui, Qi Yaxian, Sun Lingyou, Li Lingchen, Chen Xiewan, Zhu Jianbo, Sun Jianguo
Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China.
921, Hospital of PLA (Second Affiliated Hospital of Hunan Normal University), Changsha, China.
Cancer Immunol Immunother. 2025 Mar 1;74(4):128. doi: 10.1007/s00262-025-03983-8.
Immune checkpoint inhibitors (ICIs) bring cancer patients tumor control and survival benefits, yet they also trigger immune-related adverse effects (irAEs), notably checkpoint inhibitor-related pneumonitis (CIP), affecting about 5% of patients among whom 1-2% experiencing severe grade 3 or higher pneumonitis. Current research points to potential links with T cell subset dysfunction and autoantibody increase, but the specific mechanisms underlying different grades of CIP are understudied.
Herein, we employed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF) from CIP patients across varying severity levels, aiming to elucidate underlying immune environment and mechanisms of CIP progression at cellular and molecular levels.
Totally, 121,409 high qualified cells from BALF of 11 patients were annotated and categorized into five major cell types. Severe CIP (CIP-S) cases have a significant increase in the percentage of unreported epithelial cells in their bronchoalveolar lavage fluid compared with mild CIP (CIP-M) cases. These cells were defined as aberrant basaloid cells. They upregulated SOX9, increased the expression of CXCL3/5, recruited neutrophils, and activated the immune system. Additionally, macrophages in the CIP-S group had stronger antigen-presenting abilities and resulted in more CD8 + effective T cells infiltrated.
Utilizing single-cell sequencing of BALF, we discovered an enriched population of aberrant basaloid cells in CIP-S patients, which had not been previously reported. Aberrant basaloid cells may upregulate SOX9 via CXCL3/5-CXCR2 to recruit and activate neutrophils, and further activate the immune system, resulting in CIP-S. This finding could identify new targets for stratified treatment of CIP patients, holding promise of a novel approach for clinical guidance.
免疫检查点抑制剂（ICI）给癌症患者带来了肿瘤控制和生存益处，但它们也会引发免疫相关不良反应（irAE），尤其是检查点抑制剂相关肺炎（CIP），约5%的患者会受到影响，其中1%-2%会出现严重的3级或更高等级肺炎。目前的研究指出其与T细胞亚群功能障碍和自身抗体增加可能存在关联，但不同等级CIP的具体机制仍未得到充分研究。
在此，我们对不同严重程度的CIP患者的支气管肺泡灌洗液（BALF）进行了单细胞RNA测序（scRNA-seq），旨在从细胞和分子水平阐明CIP进展的潜在免疫环境和机制。
总共对11例患者BALF中的121409个高质量细胞进行了注释，并分为五种主要细胞类型。与轻度CIP（CIP-M）病例相比，严重CIP（CIP-S）病例的支气管肺泡灌洗液中未报告的上皮细胞百分比显著增加。这些细胞被定义为异常基底样细胞。它们上调了SOX9，增加了CXCL3/5的表达，招募了中性粒细胞，并激活了免疫系统。此外，CIP-S组中的巨噬细胞具有更强的抗原呈递能力，导致更多的CD8+效应T细胞浸润。
通过对BALF进行单细胞测序，我们在CIP-S患者中发现了一种此前未报告过的富集的异常基底样细胞群体。异常基底样细胞可能通过CXCL3/5-CXCR2上调SOX9，以招募和激活中性粒细胞，并进一步激活免疫系统，从而导致CIP-S。这一发现可为CIP患者的分层治疗确定新靶点，有望为临床指导提供新方法。
