Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma

Jialei Weng; Shaoqing Liu; Qiang Zhou; Wenxin Xu; Minghao Xu; Dongmei Gao; Yinghao Shen; Yong Yi; Yi Shi; Qiongzhu Dong; Chenhao Zhou; Ning Ren

doi:10.1136/jitc-2022-006655

Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma

J Immunother Cancer. 2023 Jun;11(6):e006655. doi: 10.1136/jitc-2022-006655.

Authors

Jialei Weng^{1

2}, Shaoqing Liu^{1

2}, Qiang Zhou^{1

2}, Wenxin Xu¹, Minghao Xu¹, Dongmei Gao¹, Yinghao Shen¹, Yong Yi¹, Yi Shi³, Qiongzhu Dong^{2

4}, Chenhao Zhou^{5

2}, Ning Ren^{5

2

4}

Affiliations

¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
² Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, China.
³ Biomedical Research Centre, Zhongshan Hospital Fudan University, Shanghai, China.
⁴ Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China.
⁵ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China ren.ning@zs-hospital.sh.cn zhouchenhao@fudan.edu.cn.

Abstract

Background: Hepatocellular carcinoma (HCC) is a malignancy with limited treatment options and poor prognosis. Macrophages are enriched in the HCC microenvironment and have a significant impact on disease progression and therapy efficacy. We aim to identify critical macrophages subsets involved in HCC development.

Methods: Macrophage-specific marker genes were identified through single-cell RNA sequencing analyses. The clinical significance of macrophages with palmitoyl-protein thioesterase 1 (PPT1) positive was investigated in 169 patients with HCC from Zhongshan Hospital using immunohistochemistry and immunofluorescence. The immune microenvironment of HCC and the functional phenotype of PPT1⁺ macrophages were explored using cytometry by time-of-flight (CyTOF) and RNA sequencing.

Results: Single-cell RNA sequencing analyses revealed that PPT1 was predominantly expressed in macrophages in HCC. Intratumoral PPT1⁺ macrophages abundance was associated with inferior survival durations of patients and an independent risk factor of prognosis for HCC. High throughput analyses of immune infiltrates showed that PPT1⁺ macrophage-enriched HCCs were characterized by high infiltration of CD8⁺ T cells with increased programmed death-1 (PD-1) expression. PPT1⁺ macrophages exhibited higher galectin-9, CD172a, and CCR2 levels but lower CD80 and CCR7 levels than PPT1^- macrophages. Pharmacological inhibition of PPT1 by DC661 suppressed mitogen-activated protein kinase (MAPK) pathway activity but activated nuclear factor kappa B (NF-κB) pathway in macrophages. In addition, DC661 enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model.

Conclusions: PPT1 is mainly expressed in macrophages in HCC and promotes immunosuppressive transformation of macrophages and tumor microenvironment. PPT1⁺ macrophage infiltration is associated with poor prognosis of patients with HCC. Targeting PPT1 may potentiate the efficacy of immunotherapy for HCC.

Keywords: Immunotherapy; Liver Neoplasms; Macrophages; Tumor Biomarkers; Tumor Microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Carcinoma, Hepatocellular* / therapy
Immunosuppressive Agents
Immunotherapy
Liver Neoplasms* / therapy
Mice
Tumor Microenvironment

Substances

palmitoyl-protein thioesterase
Immunosuppressive Agents