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

Nat Commun. 2021 Nov 17;12(1):6655. doi: 10.1038/s41467-021-26821-8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • DNA Copy Number Variations
  • Exome Sequencing
  • Female
  • Genetic Heterogeneity
  • HLA Antigens / genetics
  • Humans
  • Interferon-gamma / immunology
  • Loss of Heterozygosity
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / genetics
  • Small Cell Lung Carcinoma / genetics*
  • Small Cell Lung Carcinoma / immunology
  • Small Cell Lung Carcinoma / pathology
  • Survival Analysis
  • T-Lymphocytes / immunology*


  • HLA Antigens
  • IFNG protein, human
  • Receptors, Antigen, T-Cell
  • Interferon-gamma