Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer

Ming Chen (), Runzhe Chen, Ying Jin, Jun Li, Xin Hu, Jiexin Zhang, Junya Fujimoto, Shawna M. Hubert, Carl M. Gay, Bo Zhu, Yanhua Tian, Nicholas McGranahan, Won-Chul Lee, Julie George, Xiao Hu, Yamei Chen, Meijuan Wu, Carmen Behrens, Chi-Wan Chow, Hoa H. N. Pham, Junya Fukuoka, Jia Wu, Edwin Roger Parra, Latasha D. Little, Curtis Gumbs, Xingzhi Song, Chang-Jiun Wu, Lixia Diao, Qi Wang, Robert Cardnell, Jianhua Zhang, Jing Wang, Xiuning Le, Don L. Gibbons, John V. Heymach, J. Jack Lee, William N. William, Chao Cheng, Bonnie Glisson, Ignacio Wistuba, P. Andrew Futreal, Roman K. Thomas (), Alexandre Reuben (), Lauren A. Byers () and Jianjun Zhang ()
Additional contact information
Ming Chen: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University
Runzhe Chen: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University
Ying Jin: The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Jun Li: the University of Texas MD Anderson Cancer Center
Xin Hu: the University of Texas MD Anderson Cancer Center
Jiexin Zhang: the University of Texas MD Anderson Cancer Center
Junya Fujimoto: the University of Texas MD Anderson Cancer Center
Shawna M. Hubert: the University of Texas MD Anderson Cancer Center
Carl M. Gay: the University of Texas MD Anderson Cancer Center
Bo Zhu: the University of Texas MD Anderson Cancer Center
Yanhua Tian: the University of Texas MD Anderson Cancer Center
Nicholas McGranahan: Cancer Research United Kingdom-University College London Lung Cancer Centre of Excellence
Won-Chul Lee: the University of Texas MD Anderson Cancer Center
Julie George: Faculty of Medicine and University Hospital Cologne, University of Cologne
Xiao Hu: The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Yamei Chen: The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Meijuan Wu: The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Carmen Behrens: the University of Texas MD Anderson Cancer Center
Chi-Wan Chow: the University of Texas MD Anderson Cancer Center
Hoa H. N. Pham: Nagasaki University Graduate school of Biomedical Sciences
Junya Fukuoka: Nagasaki University Graduate school of Biomedical Sciences
Jia Wu: the University of Texas MD Anderson Cancer Center
Edwin Roger Parra: the University of Texas MD Anderson Cancer Center
Latasha D. Little: the University of Texas MD Anderson Cancer Center
Curtis Gumbs: the University of Texas MD Anderson Cancer Center
Xingzhi Song: the University of Texas MD Anderson Cancer Center
Chang-Jiun Wu: the University of Texas MD Anderson Cancer Center
Lixia Diao: the University of Texas MD Anderson Cancer Center
Qi Wang: the University of Texas MD Anderson Cancer Center
Robert Cardnell: the University of Texas MD Anderson Cancer Center
Jianhua Zhang: the University of Texas MD Anderson Cancer Center
Jing Wang: the University of Texas MD Anderson Cancer Center
Xiuning Le: the University of Texas MD Anderson Cancer Center
Don L. Gibbons: the University of Texas MD Anderson Cancer Center
John V. Heymach: the University of Texas MD Anderson Cancer Center
J. Jack Lee: the University of Texas MD Anderson Cancer Center
William N. William: the University of Texas MD Anderson Cancer Center
Chao Cheng: Baylor College of Medicine
Bonnie Glisson: the University of Texas MD Anderson Cancer Center
Ignacio Wistuba: the University of Texas MD Anderson Cancer Center
P. Andrew Futreal: the University of Texas MD Anderson Cancer Center
Roman K. Thomas: Medical Faculty, University of Cologne
Alexandre Reuben: the University of Texas MD Anderson Cancer Center
Lauren A. Byers: the University of Texas MD Anderson Cancer Center
Jianjun Zhang: the University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.

Date: 2021
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DOI: 10.1038/s41467-021-26821-8

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