Journal
CANCER SCIENCE
Volume 109, Issue 1, Pages 43-53Publisher
WILEY
DOI: 10.1111/cas.13424
Keywords
CD8; gastric cancer; IFN-; PD-L1; TILs
Categories
Funding
- National Research Foundation Singapore
- Singapore Ministry of Education
- Clinician Scientist-Individual Research Grant [NMRC/CIRG/1364/2013]
- Clinician Scientist Award [NMRC/CSA/0043/2012]
- Grants-in-Aid for Scientific Research [17K10540] Funding Source: KAKEN
- National Institute on Minority Health and Health Disparities [U54MD007586] Funding Source: NIH RePORTER
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Despite multidisciplinary treatment for patients with advanced gastric cancer, their prognosis remains poor. Therefore, the development of novel therapeutic strategies is urgently needed, and immunotherapy utilizing anti-programmed death 1/-programmed death ligand-1 mAb is an attractive approach. However, as there is limited information on how programmed death ligand-1 is upregulated on tumor cells within the tumor microenvironment, we examined the mechanism of programmed death ligand-1 regulation with a particular focus on interferon gamma in an invitro setting and in clinical samples. Our invitro findings showed that interferon gamma upregulated programmed death ligand-1 expression on solid tumor cells through the JAK-signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen-specific CTL against tumor cells. Following treatment of cells with anti-programmed death ligand-1 mAb after interferon gamma-pre-treatment, the reduced anti-tumor CTL activity by interferon gamma reached a higher level than the non-treatment control targets. In contrast, programmed death ligand-1 expression on tumor cells also significantly correlated with epithelial-mesenchymal transition phenotype in a panel of solid tumor cells. In clinical gastric cancer samples, tumor membrane programmed death ligand-1 expression significantly positively correlated with the presence of CD8-positive T cells in the stroma and interferon gamma expression in the tumor. The results suggest that gastric cancer patients with high CD8-positive T-cell infiltration may be more responsive to anti-programmed death 1/-programmed death ligand-1 mAb therapy.
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