Gene expression signatures as candidate biomarkers of response to PD-1 blockade in non-small cell lung cancers

Tomoiki Aiba; Chieko Hattori; Jun Sugisaka; Hisashi Shimizu; Hirotaka Ono; Yutaka Domeki; Ryohei Saito; Sachiko Kawana; Yosuke Kawashima; Keisuke Terayama; Yukihiro Toi; Atsushi Nakamura; Shinsuke Yamanda; Yuichiro Kimura; Yutaka Suzuki; Atsushi Niida; Shunichi Sugawara

doi:10.1371/journal.pone.0260500

Gene expression signatures as candidate biomarkers of response to PD-1 blockade in non-small cell lung cancers

PLoS One. 2021 Nov 29;16(11):e0260500. doi: 10.1371/journal.pone.0260500. eCollection 2021.

Authors

Tomoiki Aiba¹, Chieko Hattori¹, Jun Sugisaka¹, Hisashi Shimizu¹, Hirotaka Ono¹, Yutaka Domeki¹, Ryohei Saito¹, Sachiko Kawana¹, Yosuke Kawashima¹, Keisuke Terayama¹, Yukihiro Toi¹, Atsushi Nakamura¹, Shinsuke Yamanda¹, Yuichiro Kimura¹, Yutaka Suzuki², Atsushi Niida³, Shunichi Sugawara¹

Affiliations

¹ Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan.
² Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
³ Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / genetics
Cohort Studies
Female
Gene Expression Regulation, Neoplastic / drug effects*
Humans
Immune Checkpoint Inhibitors / therapeutic use*
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics
Male
Middle Aged
Nivolumab / therapeutic use*
Transcriptome / drug effects*

Substances

Immune Checkpoint Inhibitors
Nivolumab

Grants and funding

Our study was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb Co. The companies made a contract with our hospital directly to support our study only in terms of funding, and have had no input into the conception, conduct or reporting of our study. We don’t have any grant number for the awards: instead, we have just a written contract. This contract was made in the name of Sendai Kousei Hospital, where the principal investigator of our study is Dr. Shunichi Sugawara. We hence have declared this funding as COI of Dr. Sugawara. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.