PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer. (April 2023)

• Record Type: Journal Article
• Authors: Nakasuka, Takamasa; Ohashi, Kadoaki; Nishii, Kazuya; Hirabae, Atsuko; Okawa, Sachi; Tomonobu, Nahoko; Takada, Kenji; Ando, Chihiro; Watanabe, Hiromi; Makimoto, Go; Ninomiya, Kiichiro; Fujii, Masanori; Kubo, Toshio; Ichihara, Eiki; Hotta, Katsuyuki; Tabata, Masahiro; Kumon, Hiromi; Maeda, Yoshinobu; Kiura, Katsuyuki
• Is Part Of: Lung cancer. Volume 178(2023)
• Page Start: 1
• Page End: 10
• Publication Date: 2023-04
• Subjects: Ad-REIC genetically engineered adenovirus vector expressing the tumor suppressing gene REIC -- Ad-CAG-LacZ adenoviral vector carrying the LacZ gene with CAG -- EGFR epidermal growth factor receptor -- FCM flow cytometry -- ICD immunogenic cancer cell death -- ICIs immune checkpoint inhibitors -- IHC immunohistochemistry -- NSCLCs non-small cell lung cancers -- PBS phosphate buffered saline -- PD-1 anti-programmed cell death-1 -- PD-L1 anti-PD-1 ligand 1 -- REIC reduced expression in immortalized cells -- TME tumor microenvironment -- TKIs tyrosine kinase inhibitors; EGFR mutation -- Non-small cell lung cancer -- Antitumor immunity -- Non-inflamed tumor -- Ad-SGE-REIC -- Gene therapy -- PD-1; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2023.01.018
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Synergistic effects of Ad-SGE-REIC and PD-1 blockade were examined in a mouse model. Ad-SGE-REIC triggered systemic antitumor immunity by modifying tumor microenvironment. Addition of PD-1 blockade enhanced antitumor immunity in Egfr- mutant lung cancer. Abstract: Objectives: 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. Materials and methods: 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. Results: 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. Conclusion: 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.