| 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 |
| cfDNA |
| EGFR-mutant NSCLC |
| EGFR-TKIs |
| 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 |
| URI: | http://hdl.handle.net/2115/88796 |
| 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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