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.
Int J Oncol. 2022 Dec;61(6). doi: 10.3892/ijo.2022.5436. Epub 2022 Oct 7.
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 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.
吉非替尼是一种治疗表皮生长因子受体（EGFR）酪氨酸激酶结构域体细胞激活突变的非小细胞肺癌（NSCLC）的敏感且有效的药物。在本研究中，通过 NSCLC 细胞与外周血单个核细胞（PBMCs）的共培养，发现了吉非替尼在 EGFR 突变型 NSCLC 细胞中的新作用机制。吉非替尼显著增强了表达突变型 EGFR 的 NSCLC 细胞对 PBMCs 的细胞毒性，但对表达野生型 EGFR 的细胞没有作用。此外，观察到 EGFR 突变型细胞中 B7H5 的表达明显低于野生型细胞，而吉非替尼抑制 EGFR 或使用小干扰 RNA（siRNA）降低 EGFR 表达均可增加 EGFR 突变型 NSCLC 细胞中 B7H5 的表达。此外，当用 siRNA 降低 B7H5 的表达时，吉非替尼在 PBMCs 和 EGFR 突变型 NSCLC 细胞共培养中的毒性作用降低。此外，siRNA 介导的 PBMCs 中 B7H5 受体 CD28H 的表达降低也降低了吉非替尼对 EGFR 突变型 NSCLC 的毒性。基于这些结果，可能提出当 EGFR 过度激活时，B7H5/CD28H 轴参与 NSCLC 介导的免疫抑制。吉非替尼积极抑制突变型 EGFR，从而诱导 NSCLC 细胞表面 B7H5 的表达，激活免疫细胞中的 CD28H 信号，随后增强对 NSCLC 的细胞毒性。本研究不仅为 EGFR 突变介导的免疫逃逸机制提供了新的见解，还为免疫治疗确定了新的靶点。
