TY - JOUR
T1 - Suppression of tumor immune microenvironment via microRNA-1 after epidermal growth factor receptor-tyrosine kinase inhibitor resistance acquirement in lung adenocarcinoma
AU - Kawana, Sachiko
AU - Saito, Ryoko
AU - Miki, Yasuhiro
AU - Kimura, Yuichiro
AU - Abe, Jiro
AU - Sato, Ikuro
AU - Endo, Mareyuki
AU - Sugawara, Shunichi
AU - Sasano, Hironobu
N1 - Funding Information:
The authors thank Mr. Katsuhiko Ono (Tohoku University School of Medicine), Dr. Jun-ichi Akahira, Mr. Kikuo Narita (Sendai Kousei Hospital), and Kuniko Komuro (Miyagi Cancer Center) for their excellent technical supports. We also thank Biomedical Research Unit of Tohoku University Hospital for technical support of RT-PCR for miRNA. We would like to thank Editage (www.editage.com) for English language editing.
Funding Information:
This work was supported by JSPS KAKENHI Grant Numbers JP18 K15076.
Publisher Copyright:
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PY - 2021/1
Y1 - 2021/1
N2 - Immunotherapy is considered one of the most important therapeutic strategies for patients with lung adenocarcinoma after the development of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. However, useful predictors of immunotherapy for these patients has not been examined well, although the status of the tumor immune microenvironment (TIME), including programmed death-ligand 1 expression and lymphocyte infiltration, has been generally known to provide predictive markers for the efficacy of immunotherapy. This study aimed to clarify novel predictors of immunotherapy following EGFR-TKI resistance in lung adenocarcinoma, especially regarding micro RNA (miRNA). We evaluated the correlation between EGFR-TKI resistance and lymphocyte infiltration, before and after acquiring EGFR-TKI resistance, in 21 cases of lung adenocarcinoma, and further explored this by in vitro studies, using miRNA PCR arrays. Subsequently, we transfected miRNA-1 (miR-1), the most variable miRNA in this array, into three kinds of lung cancer cells, and examined the effects of miR-1 on EGFR-TKI sensitivity, cytokine expression and lymphocyte migration. Histopathological examination demonstrated that infiltration levels of CD8-positive T cells were significantly decreased after development of EGFR-TKI resistance. In vitro studies revealed that miR-1 significantly inhibited EGFR-TKI effect and induction of cytokines, such as C-C motif chemokine ligand 5 and C-X-C motif chemokine ligand 10, causing inhibition of monocyte migration. These results indicate that the upregulated miR-1 might suppress the TIME, following development of EGFR-TKI resistance. Therefore, miR-1 could be a clinically useful marker to predict therapeutic efficacy of immunotherapy in lung adenocarcinoma patients with EGFR-TKI resistance.
AB - Immunotherapy is considered one of the most important therapeutic strategies for patients with lung adenocarcinoma after the development of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. However, useful predictors of immunotherapy for these patients has not been examined well, although the status of the tumor immune microenvironment (TIME), including programmed death-ligand 1 expression and lymphocyte infiltration, has been generally known to provide predictive markers for the efficacy of immunotherapy. This study aimed to clarify novel predictors of immunotherapy following EGFR-TKI resistance in lung adenocarcinoma, especially regarding micro RNA (miRNA). We evaluated the correlation between EGFR-TKI resistance and lymphocyte infiltration, before and after acquiring EGFR-TKI resistance, in 21 cases of lung adenocarcinoma, and further explored this by in vitro studies, using miRNA PCR arrays. Subsequently, we transfected miRNA-1 (miR-1), the most variable miRNA in this array, into three kinds of lung cancer cells, and examined the effects of miR-1 on EGFR-TKI sensitivity, cytokine expression and lymphocyte migration. Histopathological examination demonstrated that infiltration levels of CD8-positive T cells were significantly decreased after development of EGFR-TKI resistance. In vitro studies revealed that miR-1 significantly inhibited EGFR-TKI effect and induction of cytokines, such as C-C motif chemokine ligand 5 and C-X-C motif chemokine ligand 10, causing inhibition of monocyte migration. These results indicate that the upregulated miR-1 might suppress the TIME, following development of EGFR-TKI resistance. Therefore, miR-1 could be a clinically useful marker to predict therapeutic efficacy of immunotherapy in lung adenocarcinoma patients with EGFR-TKI resistance.
KW - EGFR-TKI resistance
KW - immunotherapy predictor
KW - miR-1
KW - tumor immune microenvironment
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U2 - 10.1002/cam4.3639
DO - 10.1002/cam4.3639
M3 - Article
C2 - 33305905
AN - SCOPUS:85097378014
VL - 10
SP - 718
EP - 727
JO - Cancer Medicine
JF - Cancer Medicine
SN - 2045-7634
IS - 2
ER -