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Tumor mutation burden and immunological, genomic, and clinicopathological factors as biomarkers for checkpoint inhibitor treatment of patients with non-small-cell lung cancer

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Abstract

Cancer treatment using immune checkpoint inhibitors is widely used, although biomarkers predictive of response are not well established. However, both the expressions of programmed cell death ligand 1 (PD-L1) and the tumor mutation burden (TMB) hold promise as such biomarkers for immune checkpoint inhibitors; however, its characteristics and clinical and immunological impacts have not been fully analyzed. We, therefore, evaluated the clinical and immunological parameters related to TMB to identify potential new biomarkers. We enrolled 92 patients with non-small-cell lung cancer who underwent surgery at Fukushima Medical University Hospital from 2013 to 2016. TMB of individual tumors was calculated by whole-exome sequencing analysis. Major cancer-related gene mutations were evaluated using panel sequencing. Expression of PD-L1 and abundance of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry using surgical samples. The median TMB value was 60. TMB was significantly higher in men, current or former smokers, and in patients with squamous cell carcinoma, tumor size ≥ 2.8 cm, wild-type EGFR, TP53 gene mutation-positive status, and cyclin-dependent kinase-inhibitor gene 2A mutation-positive status. According to multivariate analysis, TMB was significantly associated with EGFR gene mutation-negative status (p = 0.0111) and TP53 gene mutation-positive status (p = 0.0425). If TMB is identified as a robust biomarker for immune checkpoint inhibitor administration, analysis of TP53 and EGFR mutations may provide a relatively rapid and easy proxy for predicting TMB.

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Abbreviations

MSI:

Microsatellite instability

NGS:

Next-generation sequencing

NSCLC:

Non-small-cell lung cancer

PD-1:

Programmed cell death 1

PD-L1:

Programmed death ligand 1

TIL:

Tumor-infiltrating lymphocyte

TMB:

Tumor mutation burden

TP53:

Tumor protein 53

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Acknowledgements

We thank Ms. Kikuta, Ms. Otomo, and Ms. Otsuki for excellent technical support for this study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Chest Surgery, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan

    Yuki Ozaki, Satoshi Muto, Hironori Takagi, Masayuki Watanabe, Takuya Inoue, Mitsuro Fukuhara, Takumi Yamaura, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Ohsugi, Mika Hoshino, Yutaka Shio & Hiroyuki Suzuki

  2. Translational Research Center, Fukushima Medical University, Fukushima, Japan

    Daisuke Tanaka, Hideaki Nanamiya, Jun-ichi Imai, Takao Isogai & Shinya Watanabe

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  1. Yuki Ozaki
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Contributions

YO and HS designed the study. YO wrote the initial draft of the manuscript. SM, DT, HN, JI, TI, and SW contributed to analysis and interpretation of data, and assisted in the preparation of the manuscript. SM, HT, MW, TI, MF, TY, NO, YM, TH, JO, MH, and YS contributed to data collection and interpretation, and critically reviewed the manuscript. All authors approved the final version of the manuscript, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Hiroyuki Suzuki.

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The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

This study was approved by the Institutional Ethics Committee at Fukushima Medical University (No. 2538). Whole-exome sequencing by next-generation sequencing was performed in accordance with the Ethical Guidelines for Human Genome and Genetic Analysis Research.

Informed consent

Patients with lung cancer provided written informed consent for the use (including the use for NGS) of tissue specimens and clinical data for research prior to undergoing pulmonary resection at the Department of Chest Surgery of Fukushima Medical University.

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Ozaki, Y., Muto, S., Takagi, H. et al. Tumor mutation burden and immunological, genomic, and clinicopathological factors as biomarkers for checkpoint inhibitor treatment of patients with non-small-cell lung cancer. Cancer Immunol Immunother 69, 127–134 (2020). https://doi.org/10.1007/s00262-019-02446-1

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