PD‐L1 expression is mainly regulated by interferon gamma associated with JAK‐STAT pathway in gastric cancer

• DOI: 10.1111/cas.13424
• Publication Date: 2017-10-16T08:53:01Z
• Authors: Kousaku Mimura; Jun Liang Teh; Hirokazu Okayama; Kensuke Shiraishi; Ley‐Fang Kua; Vivien Koh; Duane T. Smoot; Hassan Ashktorab; Takahiro Oike; Yoshiyuki Suzuki; Zul Fazreen; Bernadette R. Asu...; Asim Shabbir; Wei‐Peng Yong; Jimmy So; Richie Soong; Koji Kono
• Keywords: PD-L1; Adult; Male; 0301 basic medicine; Epithelial-Mesenchymal Transition; IFN-?; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Interferon-gamma; 03 medical and health sciences; Stomach Neoplasms; Cell Line, Tumor; Tumor Microenvironment; Humans; TILs; Aged; Janus Kinases; Aged, 80 and over; gastric cancer; Antibodies, Monoclonal; CD8; Original Articles; Middle Aged; 3. Good health; STAT Transcription Factors; Female; Signal Transduction; T-Lymphocytes, Cytotoxic

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 in vitro setting and in clinical samples. Our in vitro 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.