Trastuzumab upregulates programmed death ligand-1 expression through interaction with NK cells in gastric cancer
Kohei Yamashita1, Masaaki Iwatsuki1,2, Noriko Yasuda-Yoshihara1
1Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Background:
The predictive significance of programmed death ligand 1 (PD-L1) for programmed death 1 (PD-1) inhibitors remains unclear in gastric cancer (GC) due to the dynamic alteration by treatments. We aimed to elucidate the effects of trastuzumab (Tmab) on PD-L1 expression in GC.
Methods:
PD-L1 expression was evaluated by multicolour flow cytometry analysis after co-culturing GG cell lines and immune cells with Tmab. IFN-γ in the co-culture experiments was quantified. Immunohistochemistry (IHC) for PD-L1 expression using clinical samples was also performed to confirm PD-L1 alteration by Tmab.
Results:
PD-L1 expression was significantly upregulated by Tmab in HER2-amplified GC cell lines co-cultured with peripheral blood mononuclear cells (PBMCs). PD-L1 upregulation by Tmab was also observed in the GC cells co-cultured with NK cells in time-dependent manner, but not with monocytes. IFN-γ concentration in conditioned media from co-cultured PBMCs and NK cells with Tmab was significantly higher and anti-IFN-γ significantly suppress the Tmab-induced PD-L1 upregulation. IHC also suggested PD-L1 upregulation after Tmab treatment.
Conclusions:
Tmab can upregulate PD-L1 expression on GC cells through interaction with NK cells. These results suggest clinical implications in the assessment of the predictive significance of PD-L1 expression for PD-1 inhibitors.
Insights
Trastuzumab treatment upregulates programmed death ligand 1 (PD-L1) in gastric cancer cells, particularly through interaction with NK cells. This finding impacts the use of PD-1 inhibitors in gastric cancer therapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- The predictive value of programmed death ligand 1 (PD-L1) for programmed death 1 (PD-1) inhibitors in gastric cancer (GC) is uncertain due to treatment-induced changes.
- Trastuzumab (Tmab) is a targeted therapy used in HER2-amplified cancers, including some gastric cancers.
Purpose of the Study:
- To investigate the effect of trastuzumab (Tmab) on PD-L1 expression in gastric cancer (GC).
- To understand the role of immune cell interactions in Tmab-mediated PD-L1 modulation.
Main Methods:
- Co-culturing of GC cell lines with immune cells (PBMCs, NK cells, monocytes) and treatment with Tmab.
- Quantification of PD-L1 expression via multicolour flow cytometry and immunohistochemistry (IHC).
- Measurement of Interferon-gamma (IFN-γ) levels in co-culture supernatants.
Main Results:
- Trastuzumab significantly upregulated PD-L1 expression in HER2-amplified GC cell lines co-cultured with PBMCs and NK cells, in a time-dependent manner.
- PD-L1 upregulation was associated with increased IFN-γ levels, and anti-IFN-γ antibodies suppressed this effect.
- IHC analysis corroborated PD-L1 upregulation following Tmab treatment in clinical samples.
Conclusions:
- Trastuzumab enhances PD-L1 expression on gastric cancer cells, primarily via interaction with Natural Killer (NK) cells.
- These findings suggest that Tmab influences the tumor microenvironment and has implications for predicting response to PD-1 inhibitors in gastric cancer.
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