Pan-Cancer Analysis Identifies Tumor Cell Surface Targets for CAR-T Cell Therapies and Antibody Drug Conjugates

Xinhui Li; Jian Zhou; Weiwen Zhang; Wenhua You; Jun Wang; Linlin Zhou; Lei Liu; Wei-Wei Chen; Hanjie Li

doi:10.3390/cancers14225674

Pan-Cancer Analysis Identifies Tumor Cell Surface Targets for CAR-T Cell Therapies and Antibody Drug Conjugates

Cancers (Basel). 2022 Nov 18;14(22):5674. doi: 10.3390/cancers14225674.

Authors

Xinhui Li¹, Jian Zhou², Weiwen Zhang³, Wenhua You^{4

5}, Jun Wang⁶, Linlin Zhou⁷, Lei Liu⁸, Wei-Wei Chen⁹, Hanjie Li⁶

Affiliations

¹ State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
² Institute of Hepatology, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
³ Department of Gynaecology and Obstetrics, Shenzhen University General Hospital, Shenzhen 518055, China.
⁴ School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
⁵ Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing 211166, China.
⁶ CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
⁷ College of Medical Sciences, Qingdao Binhai University, Qingdao 266555, China.
⁸ Shenzhen Key Laboratory of Pathogen and Immunity, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen 518112, China.
⁹ Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong SAR 999077, China.

Abstract

Tumor cells can be recognized through tumor surface antigens by immune cells and antibodies, which therefore can be used as drug targets for chimeric antigen receptor-T (CAR-T) therapies and antibody drug conjugates (ADCs). In this study, we aimed to identify novel tumor-specific antigens as targets for more effective and safer CAR-T cell therapies and ADCs. Here, we performed differential expression analysis of pan-cancer data obtained from the Cancer Genome Atlas (TCGA), and then performed a series of conditional screenings including Cox regression analysis, Pearson correlation analysis, and risk-score calculation to find tumor-specific cell membrane genes. A tumor tissue-specific and highly expressed gene set containing 3919 genes from 17 cancer types was obtained. Moreover, the prognostic roles of these genes and the functions of these highly expressed membrane proteins were assessed. Notably, 427, 584, 431 and 578 genes were identified as risk factors for LIHC, KIRC, UCEC, and KIRP, respectively. Functional enrichment analysis indicated that these tumor-specific surface proteins might confer tumor cells the ability to invade and metastasize. Furthermore, correlation analysis displayed that most overexpressed membrane proteins were positively correlated to each other. In addition, 371 target membrane protein-coding genes were sifted out by excluding proteins expressed in normal tissues. Apart from the identification of well-validated genes such as GPC3, MSLN and EGFR in the literature, we further confirmed the differential protein expression of 23 proteins: ADD2, DEF6, DOK3, ENO2, FMNL1, MICALL2, PARVG, PSTPIP1, FERMT1, PLEK2, CD109, GNG4, MAPT, OSBPL3, PLXNA1, ROBO1, SLC16A3, SLC26A6, SRGAP2, and TMEM65 in four types of tumors. In summary, our findings reveal novel tumor-specific antigens, which could be potentially used for next-generation CAR-T cell therapies and ADC discovery.

Keywords: antibody drug conjugates (ADCs); chimeric antigen receptor-T (CAR-T) cell; pan-cancer analysis; tumor-specific antigens (TSAs).

Abstract

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