PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer.
PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer.
复制标题
PD-1 阻断增强了 Egfr 突变型肺癌中 Ad-SGE-REIC 触发的 CD8 T 细胞依赖性抗肿瘤免疫。
DOI：
10.1016/j.lungcan.2023.01.018
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kiura K.
中科院分区：
文献类型：
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作者：
Nakasuka T;Ohashi K;Nishii K;Hirabae A;Okawa S;Tomonobu N;Takada K;Ando C;Watanabe H;Makimoto G;Ninomiya K;Fujii M;Kubo T;Ichihara E;Hotta K;Tabata M;Kumon H;Maeda Y;Kiura K.
目的尚未针对携带驱动致癌突变（例如表皮生长因子受体（EGFR）突变）的从不吸烟的肺癌患者建立免疫治疗方案。Ad-REIC是一种表达肿瘤抑制基因的基因工程腺病毒载体，在永生化细胞（REIC）中表达减少，其免疫刺激作用已在各种实体瘤的临床试验中进行了研究。然而，免疫刺激作用的Ad-REIC在EGFR突变型肺癌与非发炎的肿瘤微环境（TME）尚未explored.Materials和methodsWe使用了同基因小鼠模型开发的transplantingEGFR突变型肺癌细胞到单或双侧翼的C57 BL/6 J小鼠。Ad-SGE-REIC是一种带有增强子序列的第二代载体，仅从一侧注射到肿瘤中，并评估其抗肿瘤作用。使用免疫组织化学或流式细胞术评价肿瘤浸润细胞。Ad-SGE-REIC和PD-1阻断的协同作用也examined. ResultsAd-SGE-REIC注射到一侧的肿瘤诱导不仅局部抗肿瘤作用，但也在非注射肿瘤，位于另一侧的旁观者的abscopal效应。PD-1+ CD 8 +T细胞的数量在注射和未注射的肿瘤中均增加。PD-1阻断可通过增加Egfr突变型肿瘤TME中CD 8 +T细胞的数量来增强Ad-SGE-REIC的局部和远端抗肿瘤作用。CD 8+细胞的耗竭恢复了抗肿瘤作用，表明它们有助于抗肿瘤immunity.ConclusionAd-SGE-REIC诱导全身抗肿瘤免疫通过修改TME状态从非炎症到炎症，与CD 8 +T细胞的浸润。此外，在Egfr突变型肺癌中，PD-1阻断增强了这种作用。这些发现为建立一种新的Ad-SGE-REIC和抗PD-1抗体的联合免疫治疗策略铺平了道路，用于非炎症TME的肺癌。
ObjectivesNo 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 inEGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored.Materials and methodsWe used a syngeneic mouse model developed by transplantingEgfr-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.ResultsInjection 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 ofEgfr-mutant tumors. Depletion of CD8+cells reverted the antitumor effect, suggesting they contribute to antitumor immunity.ConclusionAd-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+T cells. Additionally, inEgfr-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.