Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/ijms22094710
Keywords
hepatocellular carcinoma; tumor-associated macrophages; PD-L1; anti-PD-L1
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Education [NRF-2019R1I1A1A010 59642]
- Ministry of Science and ICT [2019R1A2C3005212]
- Research Fund of Seoul St. Mary's Hospital, The Catholic University of Korea
- National Research Foundation of Korea [2019R1A2C3005212] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The study found that tumor-associated macrophages (TAMs) in the tumor microenvironment of hepatocellular carcinoma (HCC) express PD-L1, and ICI treatment can reactivate CD8(+) T cells.
A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68(+) macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8(+) T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4(+) and CD8(+) T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8(+) T cells in HCC.
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