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Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression
Published on: January 19, 2019
Oncolytic adenovirus encoding a TGF-β inhibitor synergizes with PD-1 blockade to potentiate NK cell cytotoxicity
Zhongqi Zhu1, Chonghe Xu2,3, Xiaoli Kong1
1Department of Clinical Laboratory, The Fourth Affiliated Hospital (Affiliated Chaohu Hospital) of Anhui Medical University, Chaohu, Anhui, China.
Background:
Immune checkpoint inhibitors (ICIs) are a frontline treatment for advanced non-small cell lung cancer (NSCLC), yet 80% of the patients exhibit resistance, creating an urgent need for novel therapeutic strategies. In this study, we investigated the synergistic efficacy of a triple-combination therapy comprising a PD-1 antibody, adoptive NK (natural killer) cells, and an oncolytic adenovirus Ad-anti-TGF-βRII (encoding a TGF-β inhibitor) in NSCLC xenograft mouse models.
Methods:
We investigated the combined effect of Ad-anti-TGF-βRII and NK cells on PD-1 antibody monotherapy using both in vitro cell experiments and the mouse model of NSCLC. Cytotoxicity assays, quantitative real-time PCR, and western blot analysis demonstrated that Ad-anti-TGF-βRII exhibited stronger tumor-killing activity compared to the control oncolytic adenovirus Ad-null. Furthermore, cytotoxicity assays and flow cytometry were employed to explore how the combination of Ad-anti-TGF-βRII and NK cells with PD-1 antibody promotes NK cell proliferation and activation, as well as the potent tumor-killing effect of the combination therapy. In the mouse model of NSCLC, the anti-tumor efficacy of the combination therapy was evaluated by monitoring tumor volume changes, hematoxylin and eosin (H&E) staining. The underlying mechanisms were further investigated using immunofluorescence, immunohistochemistry, quantitative real-time PCR, western blot, and flow cytometry.
Results:
The triple-combination therapy markedly inhibited tumor growth, augmented NK cell cytotoxicity and elevated the expression levels of perforin, granzyme B, and IFN-γ. Furthermore, it significantly increased lymphocyte recruitment and infiltration into tumor tissue. Comprehensive analysis demonstrated the favorable safety profile of this therapeutic regimen.
Conclusions:
Our findings suggest that the combination of a PD-1 antibody, NK cells, and the oncolytic adenovirus Ad-anti-TGF-βRII represents a promising therapeutic strategy for NSCLC by remodeling the tumor microenvironment (TME) to overcome ICI resistance.
Insights
This study shows that combining a PD-1 antibody, natural killer (NK) cells, and an oncolytic adenovirus effectively treats non-small cell lung cancer (NSCLC) in mice. This triple therapy overcomes resistance to immune checkpoint inhibitors by enhancing anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Immune checkpoint inhibitors (ICIs) are a primary treatment for advanced non-small cell lung cancer (NSCLC).
- A significant challenge is the 80% resistance rate to ICIs, necessitating novel therapeutic approaches.
- Investigating synergistic combinations is crucial for overcoming treatment resistance.
Purpose of the Study:
- To evaluate the synergistic efficacy of a triple-combination therapy for NSCLC.
- To assess the combination of a PD-1 antibody, adoptive natural killer (NK) cells, and Ad-anti-TGF-βRII oncolytic adenovirus.
- To investigate the therapeutic potential in NSCLC xenograft mouse models.
Main Methods:
- Utilized in vitro cell experiments and NSCLC mouse models.
- Conducted cytotoxicity assays, qPCR, and western blot analysis.
- Employed flow cytometry, H&E staining, immunofluorescence, and immunohistochemistry to assess efficacy and mechanisms.
Main Results:
- Triple-combination therapy significantly inhibited tumor growth in NSCLC models.
- Enhanced NK cell cytotoxicity, perforin, granzyme B, and IFN-γ expression were observed.
- Increased lymphocyte infiltration into tumor tissue and a favorable safety profile were noted.
Conclusions:
- The triple-combination therapy shows promise for treating NSCLC.
- This strategy effectively remodels the tumor microenvironment (TME) to overcome ICI resistance.
- PD-1 antibody, NK cells, and Ad-anti-TGF-βRII offer a novel therapeutic avenue for NSCLC.
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