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EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment

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Title: EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment
Authors: Shiiya, Akihiko Browse this author
Noguchi, Takuro Browse this author
Tomaru, Utano Browse this author
Ariga, Shin Browse this author
Takashima, Yuta Browse this author
Ohhara, Yoshihito Browse this author
Taguchi, Jun Browse this author
Takeuchi, Satoshi Browse this author
Shimizu, Yasushi Browse this author
Kinoshita, Ichiro Browse this author
Koizumi, Tomonobu Browse this author
Matsuno, Yoshihiro Browse this author
Shinagawa, Naofumi Browse this author
Sakakibara-Konishi, Jun Browse this author
Dosaka-Akita, Hirotoshi Browse this author →KAKEN DB
Keywords: CD24
tumor immune escape
Issue Date: Apr-2023
Publisher: John Wiley & Sons
Journal Title: Cancer science
Volume: 114
Issue: 4
Start Page: 1270
End Page: 1283
Publisher DOI: 10.1111/cas.15701
Abstract: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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