Da-Liang Ou1, Yu-Yang Lin2, Chia-Lang Hsu3, Yin-Yao Lin1, Chia-Wei Chen1, Jhang-Sian Yu4, Shi-Chuen Miaw4, Ping-Ning Hsu4, Ann-Lii Cheng1,5,6,7, Chiun Hsu1,5,6,7. 1. Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. 2. School of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. 3. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. 4. Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan. 5. National Taiwan University Cancer Center, Taipei, Taiwan. 6. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 7. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Abstract
BACKGROUND: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. METHODS: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. RESULTS: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. CONCLUSIONS: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.
BACKGROUND: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. METHODS: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. RESULTS: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. CONCLUSIONS: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.
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