ATAD2 is a potential immunotherapy target for patients with small cell lung cancer harboring HLA-A∗0201.

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).