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

Ming Chen,Jiexin Zhang,Shawna M Hubert,Lauren A Byers,Yamei Chen,J Jack Lee,Alexandre Reuben,Xin Hu,Lixia Diao,Bonnie S Glisson ,William N William,Won‐Chul Lee ,Yanhua Tian,Xiao Hu,John V Heymach,Chao Cheng,Edwin R Parra ,Carmen Behrens,Runzhe Chen,Hoa H.n Pham ,Jia Wu,Jun Li,Ignacio I Wistuba ,Latasha Little ,Ying Jin,Don L Gibbons,Roman K Thomas,Chang-Jiun Wu,Xingzhi Song,Junya Fujimoto,Qi Wang,P Andrew Futreal,Meijuan Wu,Robert J Cardnell ,Junya Fukuoka,Xiuning Le,Julie George,Bo Zhu,Nicholas Mcgranahan,Chi-Wan Chow,Curtis Gumbs

doi:10.1038/s41467-021-26821-8

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.

Highlights

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy
Around one-third of SCLC patients present with cancer confined to one hemithorax, defined as limited-stage disease (LS) that can be treated with chemotherapy combined with radiotherapy or surgical resection, while the remaining patients present with extensive-stage disease (ES) exhibiting extensive lymph node involvement and/or distant metastases usually treated with palliative chemotherapy with or without immune checkpoint blockade (ICB) therapy[4,5,6]
A median of 80.1% (28–93%) (interquartile (25th–75th) range: 72–84%) of mutations were mapped to the trunks of these 18 SCLCs (Fig. 1a) representing ubiquitous mutations present in all regions within the same tumors, compared with 72% (8–99.6%) (interquartile (25th–75th) range: 55–84%) trunk mutations in 100 early-stage non-small cell lung cancers (NSCLCs) in TRACERx cohort (p = 0.218)[14]

Summary

Introduction

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. We demonstrate that despite a homogeneous genomic landscape, SCLC exhibits a cold and heterogeneous T-cell infiltration associated with higher chromosomal copy number aberration (CNA) burden and loss of essential immune genes, potentially leading to ineffective antitumor immune surveillance and inferior survival.

Results

Conclusion