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Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression
Published on: January 19, 2019
PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer
Takamasa Nakasuka1, Kadoaki Ohashi2, Kazuya Nishii1
1Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
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.
Insights
Ad-SGE-REIC gene therapy demonstrated local and systemic antitumor effects in EGFR-mutant lung cancer by increasing CD8+ T cells. Combining Ad-SGE-REIC with PD-1 blockade enhanced these effects, offering a new immunotherapy strategy.
Area of Science:
- Oncology
- Immunotherapy
- Gene Therapy
Background:
- No established immunotherapy exists for never-smokers with EGFR-mutant lung cancer.
- Ad-REIC has shown immunostimulatory effects in various solid tumors.
- The effect of Ad-REIC on EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) is unexplored.
Purpose of the Study:
- To investigate the antitumor effects of Ad-SGE-REIC in EGFR-mutant lung cancer.
- To evaluate the combination therapy of Ad-SGE-REIC and PD-1 blockade.
- To explore the impact on the tumor microenvironment and immune cell infiltration.
Main Methods:
- A syngeneic mouse model of EGFR-mutant lung cancer was used.
- Ad-SGE-REIC was injected into tumors, and antitumor effects were assessed.
- Tumor-infiltrating cells, including CD8+ T cells, were analyzed via immunohistochemistry and flow cytometry.
- Synergistic effects with PD-1 blockade were examined.
Main Results:
- Ad-SGE-REIC induced local and abscopal antitumor effects.
- The treatment increased PD-1+CD8+ T cells in both injected and non-injected tumors.
- PD-1 blockade enhanced Ad-SGE-REIC's effects by increasing CD8+ T cell infiltration.
- CD8+ T cell depletion abrogated the antitumor effect.
Conclusions:
- Ad-SGE-REIC converts non-inflamed TME to inflamed, promoting systemic immunity via CD8+ T cells.
- Combination therapy with Ad-SGE-REIC and anti-PD-1 antibody shows promise for EGFR-mutant lung cancer.
- This strategy could establish a novel immunotherapy for lung cancer with non-inflamed TME.
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