Trastuzumab upregulates programmed death ligand-1 expression through interaction with NK cells in gastric cancer

• Published in: British journal of cancer Vol. 124; no. 3; pp. 595 - 603
• Main Authors: Yamashita, Kohei, Iwatsuki, Masaaki, Yasuda-Yoshihara, Noriko, Morinaga, Takeshi, Nakao, Yosuke, Harada, Kazuto, Eto, Kojiro, Kurashige, Junji, Hiyoshi, Yukiharu, Ishimoto, Takatsugu, Nagai, Yohei, Iwagami, Shiro, Baba, Yoshifumi, Miyamoto, Yuji, Yoshida, Naoya, Ajani, Jaffer A., Baba, Hideo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.02.2021; Nature Publishing Group
• Subjects: 631/67/1059/2325; 631/67/1504/1829; Antineoplastic Agents, Immunological - pharmacology; Apoptosis; B7-H1 Antigen - drug effects; B7-H1 Antigen - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Communication; Cell culture; Cell Line, Tumor; Coculture Techniques; Culture Media, Conditioned; Death; Drug Resistance; Epidemiology; ErbB-2 protein; Flow Cytometry; Gastric cancer; Humans; Immunohistochemistry; Immunotherapy; Interferon-gamma - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Leukocytes (mononuclear); Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Ligands; Molecular Medicine; Monoclonal antibodies; Monocytes; Oncology; PD-1 protein; PD-L1 protein; Peripheral blood mononuclear cells; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Stomach Neoplasms - metabolism; Targeted cancer therapy; Trastuzumab; Trastuzumab - pharmacology; Up-Regulation - drug effects; γ-Interferon
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-01138-3

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.