EBioMedicine · 2025
ATAD2 is a potential immunotherapy target for patients with small cell lung cancer harboring HLA-A∗0201.
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Yuan Li, Li Sini, Zhu Yixiang, Yang Lin, Zhang Xue, Qu Yan, Wang Zhijie, Duan Jianchun, Zhong Jia, Tian Yanhua, Liu Lihui, Sun Boyang, Fei Kailun, Liu Zheng, Zhang Jian, He Yan, Guo Yufeng, He DanMing, Zhuang Wei, Zhang Jinsong, Ma Zixiao, Bai Hua, Wang Jie
Аннотация
BACKGROUND: Small cell lung cancer (SCLC) 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 (LC-MS/MS) to analyse cancer/testis antigens (CTAs) 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 (NSCLC), 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 (ATAD2) 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 (ASCL1) 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 (2022YFC2505000); National Natural Science Foundation of China (NSFC) general program (82272796) NSFC special program (82241229); CAMS Innovation Fund for Medical Sciences (CIFMS 2022-I2M-1-009); CAMS Key Laboratory of Translational Research on Lung Cancer (2018PT31035); Aiyou foundation (KY201701). National key R&D program of China (2022YFC2505004). NSFC general program (81972905). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022012).
METHODS: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyse cancer/testis antigens (CTAs) 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 (NSCLC), 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 (ATAD2) 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 (ASCL1) 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 (2022YFC2505000); National Natural Science Foundation of China (NSFC) general program (82272796) NSFC special program (82241229); CAMS Innovation Fund for Medical Sciences (CIFMS 2022-I2M-1-009); CAMS Key Laboratory of Translational Research on Lung Cancer (2018PT31035); Aiyou foundation (KY201701). National key R&D program of China (2022YFC2505004). NSFC general program (81972905). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022012).