Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma
2021
Dong-Jun Park | Pil-Soo Sung | Gil-Won Lee | Sungwoo Cho | Sung-Min Kim | Byung-Yoon Kang | Wonhee Hur | Hyun Yang | Soon-Kyu Lee | Sung-Hak Lee | Eun-Sun Jung | Chang-Ho Seo | Joseph Ahn | Ho-Joong Choi | Young-Kyoung You | Jeong-Won Jang | Si-Hyun Bae | Jong-Young Choi | Seung-Kew Yoon
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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> and CD8<sup>+</sup> 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<sup>+</sup> T cells in HCC.
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