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 Pham, Junya Fukuoka, Jia Wu, Edwin R. Parra, Latasha Little, Curtis Gumbs, Xingzhi Song, Chang‐Jiun Wu, Lixia Diao, Qi Wang, Robert J. Cardnell, Jianhua Zhang, Jing Wang, Xiuning Le, Don L. Gibbons, John V. Heymach, J. Jack Lee, William N. William, Chao Cheng, Bonnie S. Glisson, Ignacio I. Wistuba, P. Andrew Futreal, Roman K. Thomas, Alexandre Reuben, Lauren A. Byers, Jianjun Zhang
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.