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- Title
Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma.
- Authors
Park, Dong-Jun; Sung, Pil-Soo; Lee, Gil-Won; Cho, Sung-Woo; Kim, Sung-Min; Kang, Byung-Yoon; Hur, Won-Hee; Yang, Hyun; Lee, Soon-Kyu; Lee, Sung-Hak; Jung, Eun-Sun; Seo, Chang-Ho; Ahn, Joseph; Choi, Ho-Joong; You, Young-Kyoung; Jang, Jeong-Won; Bae, Si-Hyun; Choi, Jong-Young; Yoon, Seung-Kew; Kim, Jin-Wook
- Abstract
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.
- Subjects
PROGRAMMED cell death 1 receptors; HEPATOCELLULAR carcinoma; MACROPHAGES; T cells; IMMUNE checkpoint inhibitors; LABORATORY mice
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 9, p4710
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms22094710