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

Author:

Chen Ming,Chen Runzhe,Jin Ying,Li Jun,Hu Xin,Zhang JiexinORCID,Fujimoto Junya,Hubert Shawna M.ORCID,Gay Carl M.ORCID,Zhu Bo,Tian Yanhua,McGranahan NicholasORCID,Lee Won-Chul,George JulieORCID,Hu Xiao,Chen Yamei,Wu Meijuan,Behrens Carmen,Chow Chi-Wan,Pham Hoa H. N.ORCID,Fukuoka Junya,Wu JiaORCID,Parra Edwin RogerORCID,Little Latasha D.,Gumbs Curtis,Song Xingzhi,Wu Chang-JiunORCID,Diao LixiaORCID,Wang QiORCID,Cardnell Robert,Zhang JianhuaORCID,Wang JingORCID,Le XiuningORCID,Gibbons Don L.ORCID,Heymach John V.ORCID,Jack Lee J.ORCID,William William N.,Cheng ChaoORCID,Glisson Bonnie,Wistuba Ignacio,Andrew Futreal P.ORCID,Thomas Roman K.,Reuben AlexandreORCID,Byers Lauren A.ORCID,Zhang JianjunORCID

Abstract

AbstractSmall-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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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