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作者

Li Yuan Sini Li Yixiang Zhu Lin Yang Xue Zhang Yan Qu Zhijie Wang Jianchun Duan Jia Zhong Yanhua Tian Lihui Liu Boyang Sun Kailun Fei Zheng Liu Jian Zhang Yan He Yufeng Guo DanMing He Wei Zhuang Jinsong Zhang

作者单位

²Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China ⁴Department of Radiotherapy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China ³Department of Pathology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China ¹State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences Peking Union Medical College, Beijing, 100021, China

刊名

eBioMedicine

年份

2025

卷号

Vol.112

页码

105515

ISSN

2352-3964

关键词

Small cell lung cancer (SCLC) Cancer/testis antigens (CTAs) ATPase family AAA domain-containing protein 2 (ATAD2) HLA-A∗02:01 Immunopeptidomics YSDDDVPSV

摘要

Background Small cell lung cancer represents a highly aggressive neuroendocrine tumour with a dismal prognosis. Currently, the identification of a specific tumour antigen that can facilitate immune-based therapies for SCLC remains elusive. Methods We employed liquid chromatography–tandem mass spectrometry to analyse cancer/testis antigens in SCLC cell lines and human tumour specimens. Immunohistochemistry of clinical specimens was performed to compare protein expression in SCLC, non-small cel...更多

Background Small cell lung cancer represents a highly aggressive neuroendocrine tumour with a dismal prognosis. Currently, the identification of a specific tumour antigen that can facilitate immune-based therapies for SCLC remains elusive. Methods We employed liquid chromatography–tandem mass spectrometry to analyse cancer/testis antigens in SCLC cell lines and human tumour specimens. Immunohistochemistry of clinical specimens was performed to compare protein expression in SCLC, non-small cell lung cancer , and matched normal-adjacent tissues. Additionally, publicly available RNA sequencing databases were interrogated to identify gene expression patterns in different SCLC subtypes and in different disease stages. Findings Distinct numbers and types of CTAs were identified across SCLC subtypes, with significantly higher expression levels of ATPase family AAA domain-containing protein 2 observed in SCLC compared to normal adjacent tissues and NSCLC tissues. A dynamic expression pattern of ATAD2 was found throughout the clinical course of SCLC and exhibited a positive correlation with achaete-scute family bHLH transcription factor 1 expression in SCLC. Immunopeptidomics analysis identified the YSDDDVPSV sequence derived from the HLA-A∗02:01 restriction epitope of ATAD2 as a highly promising tumour antigen candidate for potential immunotherapy applications. YSDDDVPSV immunopeptides were confirmed to be present in SCLC-A and SCLC-N with HLA-A∗02:01 restriction. Notably, HLA-A∗02:01 T cells exhibited a robust response upon stimulation with YSDDDVPSV immunopeptide pulsed by T2 cells. Interpretation Our findings highlight the potential of targeting the ATAD2 YSDDDVPSV immunopeptide for SCLC immunotherapy, thereby offering a promising avenue for the development of adoptive T cell therapies to effectively treat ASCL1-positive or NEUROD1-positive SCLC carrying HLA-A∗02:01. Funding This study was supported by the National key R&D program of China ; National Natural Science Foundation of China general program NSFC special program ; CAMS Innovation Fund for Medical Sciences ; CAMS Key Laboratory of Translational Research on Lung Cancer ; Aiyou foundation . National key R&D program of China . NSFC general program . Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences .收起

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