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Updated: Aug 13, 2026
Semi-automatic PD-L1 Characterization and Enumeration of Circulating Tumor Cells from Non-small Cell Lung Cancer Patients by Immunofluorescence
Published on: August 14, 2019
Endogenous CD155 drives metabolic reprogramming via PI3K/AKT/HIF-1α-glycolysis axis to mediate anti-PD-1 resistance
Wei-Guang Du1, Xi-Yang Tang1, Yu-Long Zhou1
1Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Objective:
Anti-PD-1 therapy resistance remains a critical barrier in non-small cell lung cancer (NSCLC) management, and the underlying mechanisms are incompletely defined.
Methods:
We generated CD155‑knockout (KO) NSCLC cell lines using the CRISPR‑Cas9 system and performed systematic multi‑omics analyses, including single‑cell RNA‑seq, bulk RNA‑seq, proteomics, and metabolomics. The key molecular mechanisms were further validated by immunohistochemistry (IHC), western blotting, and chromatin immunoprecipitation (ChIP). Functional assays assessed cell proliferation, migration, and metabolic phenotypes, while the therapeutic efficacy was assessed in vivo using AAV9_shCD155.
Results:
Single-cell sequencing revealed aberrantly high CD155 expression in NSCLC patients with poor response to anti-PD-1 therapy. High CD155 expression in NSCLC tissues correlated with unfavourable prognosis. ETS1 was identified as a direct transcriptional driver of CD155. Multi-omics analysis and functional assays demonstrated that CD155 upregulates the expression of key glycolytic proteins (GLUT1, GLUT3, LDHB) by activating the PI3K/AKT/HIF-1α signalling axis, thereby driving glycolytic metabolism, proliferation, and migration of tumour cells. CD155 knockout significantly suppressed these malignant phenotypes. In xenograft mouse models, monotherapy with AAV9_shCD155 effectively inhibited tumour growth and postoperative recurrence. More importantly, in humanised mouse models, combining AAV9_shCD155 with pembrolizumab produced synergistic anti-tumour effects, more significantly suppressing tumour growth and promoting immune cell infiltration into the tumour microenvironment.
Conclusion:
CD155 mediates anti-PD-1 resistance by activating PI3K/AKT/HIF-1α-driven glycolytic reprogramming. Targeting CD155 combined with anti-PD-1 overcomes resistance, supporting a dual-target therapeutic strategy.
Key Points:
CD155 is identified as a key driver of anti-PD-1 resistance in NSCLC. CD155 promotes tumour glycolysis and malignant progression via the PI3K/AKT/HIF-1α signalling axis. AAV9_shCD155 combined with anti-PD-1 markedly inhibits tumour growth and promotes immune infiltration.
Insights
CD155 drives anti-PD-1 resistance in non-small cell lung cancer by promoting tumor glycolysis. Targeting CD155 with anti-PD-1 therapy offers a promising dual-target strategy to overcome resistance and inhibit tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Anti-programmed cell death protein 1 (anti-PD-1) therapy resistance is a significant challenge in non-small cell lung cancer (NSCLC) treatment.
- The molecular mechanisms underlying this resistance are not fully understood.
Purpose of the Study:
- To investigate the role of CD155 in mediating anti-PD-1 resistance in NSCLC.
- To elucidate the molecular pathways involved in CD155-driven resistance.
- To evaluate the therapeutic potential of targeting CD155 in combination with anti-PD-1 therapy.
Main Methods:
- Generated CD155-knockout NSCLC cell lines using CRISPR-Cas9.
- Conducted multi-omics analyses (single-cell RNA-seq, bulk RNA-seq, proteomics, metabolomics).
- Validated findings using immunohistochemistry, western blotting, chromatin immunoprecipitation, and in vivo models (AAV9_shCD155).
Main Results:
- High CD155 expression in NSCLC correlates with poor anti-PD-1 response and unfavorable prognosis.
- CD155 upregulates glycolysis via the PI3K/AKT/HIF-1α axis, promoting tumor cell proliferation and migration.
- CD155 knockout suppressed malignant phenotypes; AAV9_shCD155 monotherapy inhibited tumor growth.
- Combination therapy (AAV9_shCD155 + pembrolizumab) showed synergistic anti-tumor effects and increased immune cell infiltration.
Conclusions:
- CD155 is a key mediator of anti-PD-1 resistance in NSCLC through PI3K/AKT/HIF-1α-driven glycolytic reprogramming.
- Targeting CD155 in combination with anti-PD-1 therapy is a viable strategy to overcome resistance.
- This dual-target approach significantly inhibits tumor growth and enhances anti-tumor immunity.