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Clinicopathologic Features and Immune Microenvironment of Non-Small-cell Lung Cancer With Primary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

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Title: Clinicopathologic Features and Immune Microenvironment of Non-Small-cell Lung Cancer With Primary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Authors: Takashima, Yuta Browse this author
Sakakibara-Konishi, Jun Browse this author →KAKEN DB
Hatanaka, Yutaka Browse this author →KAKEN DB
Hatanaka, Kanako C. Browse this author
Ohhara, Yoshihito Browse this author
Oizumi, Satoshi Browse this author →KAKEN DB
Hida, Yasuhiro Browse this author →KAKEN DB
Kaga, Kichizo Browse this author →KAKEN DB
Kinoshita, Ichiro Browse this author →KAKEN DB
Dosaka-Akita, Hirotoshi Browse this author →KAKEN DB
Matsuno, Yoshihiro Browse this author →KAKEN DB
Nishimura, Masaharu Browse this author →KAKEN DB
Keywords: EGFR-TKI
Tumor-infiltrating lymphocytes
primary resistance
Issue Date: Jul-2018
Publisher: Elsevier
Journal Title: Clinical lung cancer
Volume: 19
Issue: 4
Start Page: 352
End Page: 359
Publisher DOI: 10.1016/j.cllc.2018.02.004
PMID: 29544718
Abstract: We evaluated the clinical and immunopathological features of non-small cell lung cancer with primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors. The rate of smoking was significantly higher in primary resistance. The immune microenvironment characterized by low total tumor infiltrating lymphocytes and negative programmed death ligand 1 correlated significantly with primary resistance.
Background: Approximately 20% to 30% of nonesmall-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumorinfiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC. However, few studies have directly focused on the relationship between the tumor immunemicroenvironment and primary resistance to EGFR-TKIs. Materials and Methods: The characteristics of 124 NSCLC patients with EGFR mutations who had received EGFR-TKIs were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFRTKI treatment were assessed for the density of TILs expressing CD4 or CD8 and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically. Results: Primary resistance was observed in 13.7% of the patients (17 of 124). A significant difference in smoking history was observed between patients with primary resistance and those with noneprimary resistance. A lower density of total TILs and negative PD-L1 expression on immunohistochemical analysis correlated significantly with primary resistance, in contrast to that with noneprimary resistance. Moreover, the negative PD-L1 expression with low TIL density, indicating immune ignorant phenotype of tumor microenvironment, was observed in those with primary resistance with a significant difference. Conclusion: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs.
Rights: © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 高島 雄太

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