Theranostics 2021; 11(14):7092-7109. doi:10.7150/thno.58039

Research Paper

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC

Yayi He1*, Linsong Chen2*, Lishu Zhao1, Shiying Dang3, Guifeng Liu3, Shinji Sasada4, Patrick C. Ma5, Nico van Zandwijk6, Rafael Rosell7, Helmut H. Popper8, Hao Wang1, Minlin Jiang1, Haoyue Guo1, Xinyi Liu3, Shifu Chen3, Xiaoni Zhang3, Mingyan Xu3, Bo Zhu9✉, Ming Liu2✉, Caicun Zhou1✉ on behalf of the AME Lung Cancer Collaborative Group

1. Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zhengmin Road, Yangpu District, Shanghai 200433, China.
2. Department of Surgery, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zhengmin Road, Yangpu District, Shanghai 200433, China.
3. HaploX Biotechnology, Co., Ltd. 8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan District, Shenzhen 518057, Guangdong, China.
4. Department of Respiratory Medicine, Tokyo Saiseikai Central Hospital, Minato-ku, Tokyo, Japan.
5. Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA, USA.
6. Sydney Local Health District, Concord Repatriation General Hospital, Concord, NSW, The University of Sydney, Australia.
7. Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra. Canyet, Badalona (Barcelona), Spain.
8. Department of Pathology, Medical University of Graz, Neue Stiftingtalstrasse 6, Graz 8036, Austria.
9. Institute of Cancer, Xinqiao Hospital, the Army Medical University, No. 83, Xinqiaozheng Street, Shapingba District, Chongqing 400037, China.
* These authors contributed equally.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
He Y, Chen L, Zhao L, Dang S, Liu G, Sasada S, Ma PC, van Zandwijk N, Rosell R, Popper HH, Wang H, Jiang M, Guo H, Liu X, Chen S, Zhang X, Xu M, Zhu B, Liu M, Zhou C. Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC. Theranostics 2021; 11(14):7092-7109. doi:10.7150/thno.58039. Available from https://www.thno.org/v11p7092.htm

File import instruction

Abstract

Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level.

Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed.

Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy.

Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

Keywords: Lung cancer, chemotherapy, immunotherapy, tumor mutational burden (TMB), programmed death-1 (PD-1), messager ribonucleic acid (mRNA).