Gefitinib enhances the anti‑tumor immune response against EGFR‑mutated NSCLC by upregulating B7H5 expression and activating T cells via CD28H

Guo,Huihui; Zhang,Xilin; Xie,Shangzhi; Chen,Tianwei; Xie,Dong; Cai,Ying; Cui,Dawei; Wang,Liang; Chen,Wei; Wang,Xiang

doi:10.3892/ijo.2022.5436

Gefitinib enhances the anti‑tumor immune response against EGFR‑mutated NSCLC by upregulating B7H5 expression and activating T cells via CD28H

Authors:
- Huihui Guo
- Xilin Zhang
- Shangzhi Xie
- Tianwei Chen
- Dong Xie
- Ying Cai
- Dawei Cui
- Liang Wang
- Wei Chen
- Xiang Wang
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Affiliations: Zhejiang Provincial Key Laboratory of Media Biology and Pathogenic Control, Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang 313000, P.R. China, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China, Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, P.R. China, Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China, Department of Thoracic Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
Published online on: October 6, 2022 https://doi.org/10.3892/ijo.2022.5436
Article Number: 146
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gefitinib is a sensitive and effective drug to treat non‑small‑cell lung cancer (NSCLC) carrying the somatic activating mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR). In the present study, a new mechanism of action of gefitinib in EGFR‑mutated NSCLC cells was discovered using in vitro co‑culture of NSCLC cells with peripheral blood mononuclear cells (PBMCs). Gefitinib significantly enhanced the cytotoxicity of PBMCs against NSCLC cells expressing mutated EGFR but not in cells expressing wild‑type EGFR. Furthermore, it was observed that B7H5 expression was significantly lower in EGFR‑mutant cells than in wild‑type cells, while inhibition of EGFR by gefitinib or reduction in EGFR using a small interfering RNA (siRNA) both increased the expression of B7H5 in EGFR‑mutated NSCLC cells. In addition, when B7H5 expression was reduced by siRNA, the toxic effect of gefitinib was reduced in the co‑culture of PBMCs and EGFR‑mutant NSCLC cells. In addition, the siRNA‑mediated decrease in expression of the B7H5 receptor CD28H in PBMCs also reduced the toxicity of gefitinib on EGFR‑mutated NSCLC. Based on these results, it may be proposed that the B7H5/CD28H axis is involved in NSCLC‑mediated immunosuppression when EGFR is overactivated. Gefitinib actively inhibits mutated EGFR, which induces B7H5 expression on the cell surface of NSCLC cells, thereby activating CD28H signaling in immune cells, followed by enhanced cytotoxicity against NSCLC. The present study not only provided new insight into the immune evasion mechanism mediated by EGFR mutations but also identified new targets for immune therapy.

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