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; Jianjun Zhang

doi:10.1038/s41467-021-26821-8

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. PhamJunya 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, Jianjun Zhang

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	6655
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26821-8
State	Published - Dec 2021

ASJC Scopus subject areas

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

MD Anderson CCSG core facilities

Biostatistics Resource Group
Bioinformatics Shared Resource

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10.1038/s41467-021-26821-8

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Chen, M., Chen, R., Jin, Y., Li, J., Hu, X., Zhang, J., Fujimoto, J., Hubert, S. M., Gay, C. M., Zhu, B., Tian, Y., McGranahan, N., Lee, W. C., George, J., Hu, X., Chen, Y., Wu, M., Behrens, C., Chow, C. W., ... Zhang, J. (2021). Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer. Nature communications, 12(1), Article 6655. https://doi.org/10.1038/s41467-021-26821-8

Chen, M, Chen, R, Jin, Y, Li, J , Hu, X , Zhang, J, Fujimoto, J, Hubert, SM, Gay, CM, Zhu, B, Tian, Y, McGranahan, N, Lee, WC, George, J, Hu, X, Chen, Y, Wu, M, Behrens, C, Chow, CW, Pham, HHN, Fukuoka, J, Wu, J , Parra, ER, Little, LD, Gumbs, C, Song, X, Wu, CJ, Diao, L , Wang, Q , Cardnell, R, Zhang, J, Wang, J , Le, X , Gibbons, DL , Heymach, JV , Jack Lee, J, William, WN, Cheng, C, Glisson, B, Wistuba, I , Andrew Futreal, P, Thomas, RK, Reuben, A , Byers, LA & Zhang, J 2021, 'Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer', Nature communications, vol. 12, no. 1, 6655. https://doi.org/10.1038/s41467-021-26821-8

@article{a7f89cfecc054dec89eec1913652d6a3,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-26821-8",

language = "English (US)",

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AU - Chen, Ming

AU - Chen, Runzhe

AU - Jin, Ying

AU - Li, Jun

AU - Hu, Xin

AU - Zhang, Jiexin

AU - Fujimoto, Junya

AU - Hubert, Shawna M.

AU - Gay, Carl M.

AU - Zhu, Bo

AU - Tian, Yanhua

AU - McGranahan, Nicholas

AU - Lee, Won Chul

AU - George, Julie

AU - Hu, Xiao

AU - Chen, Yamei

AU - Wu, Meijuan

AU - Behrens, Carmen

AU - Chow, Chi Wan

AU - Pham, Hoa H.N.

AU - Fukuoka, Junya

AU - Wu, Jia

AU - Parra, Edwin Roger

AU - Little, Latasha D.

AU - Gumbs, Curtis

AU - Song, Xingzhi

AU - Wu, Chang Jiun

AU - Diao, Lixia

AU - Wang, Qi

AU - Cardnell, Robert

AU - Zhang, Jianhua

AU - Wang, Jing

AU - Le, Xiuning

AU - Gibbons, Don L.

AU - Heymach, John V.

AU - Jack Lee, J.

AU - William, William N.

AU - Cheng, Chao

AU - Glisson, Bonnie

AU - Wistuba, Ignacio

AU - Andrew Futreal, P.

AU - Thomas, Roman K.

AU - Reuben, Alexandre

AU - Byers, Lauren A.

AU - Zhang, Jianjun

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 6655

ER -

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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