尚未建立适用于永不吸烟的肺癌携带驱动致癌基因突变（如表皮生长因子受体（EGFR）突变）的免疫治疗方案。在临床试验中研究了一种基因工程腺病毒载体，Ad-REIC，它表达肿瘤抑制基因“REIC”来减少不死细胞中的表达，其免疫刺激作用已在多种实体肿瘤中得到研究。然而，在EGFR突变的肺癌中，Ad-REIC的免疫刺激作用以及非炎症性肿瘤微环境（TME）中的作用尚未探索。我们使用移植Egfr突变型肺癌细胞到C57BL/6J小鼠的单侧或双侧瘤模型。将第二代增强子序列载体Ad-SGE-REIC注入到一个侧瘤中，评估其抗肿瘤效果。使用免疫组织化学或流式细胞术评估肿瘤浸润细胞。还检查了Ad-SGE-REIC和PD-1阻断的协同作用。向一个侧瘤注入Ad-SGE-REIC不仅诱导了局部的抗肿瘤效应，还在另一侧的未注射瘤中诱导了副作用效应。PD-1阳性CD8+ T细胞的数量在注射和未注射瘤中均增加。PD-1阻断通过增加Egfr突变瘤TME中CD8+ T细胞的数量增强了Ad-SGE-REIC的局部和副作用抗肿瘤效应。CD8+ 细胞的去除逆转了抗肿瘤效应，这表明它们对抗肿瘤免疫有贡献。 Ad-SGE-REIC通过改变TME状态，从非炎症性到炎症性，以及CD8+ T细胞的渗透诱导了全身性的抗肿瘤免疫。此外，在Egfr突变的肺癌中，PD-1阻断增强了这种效应。这些发现为使用Ad-SGE-REIC和抗-PD-1抗体建立针对非炎症性肺癌的新型联合免疫治疗策略铺平了道路。版权所有©2023年Elsevier B.V.。保留所有权利。

No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored.We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined.Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity.Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME.Copyright © 2023 Elsevier B.V. All rights reserved.