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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients
Zhiwu Tan1,2, Mei Sum Chiu3, Xinxiang Yang4
1AIDS Institute and Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, People's Republic of China zchenai@hku.hk zwtan@hku.hk kwanman@hku.hk.
Objective:
Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB.
Design:
We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models.
Results:
We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1+ T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+ T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1+ T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1+ T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models.
Conclusion:
Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.
Insights
A novel PD-1 isoform, Δ42PD-1, drives hepatocellular carcinoma (HCC) progression and resistance to PD-1 immune checkpoint blockade (ICB). Targeting Δ42PD-1 shows promise for HCC immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint blockade (ICB) has transformed cancer therapy.
- Hepatocellular carcinoma (HCC) patients often exhibit resistance to PD-1 ICB.
- The mechanisms underlying this resistance are not fully understood.
Purpose of the Study:
- To investigate the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC.
- To elucidate the contribution of Δ42PD-1 to resistance against PD-1 ICB in HCC.
- To identify potential therapeutic targets for HCC immunotherapy.
Main Methods:
- Analysis of 74 HCC patients across three cohorts (untreated, nivolumab-treated, pembrolizumab-treated).
- Immunophenotyping of peripheral blood mononuclear cells and tumor-infiltrating lymphocytes.
- Single-cell RNA sequencing, functional studies, and assessment of anti-Δ42PD-1 antibody efficacy in humanized mouse models.
Main Results:
- Identified distinct T cell subsets expressing Δ42PD-1 but not PD-1, comprising up to 71% of cytotoxic T lymphocytes in untreated HCC.
- Δ42PD-1+ T cells were tumor-infiltrating, correlated with HCC severity, and exhibited greater exhaustion.
- Anti-PD-1 ICB increased Δ42PD-1+ T cells, particularly in progressive disease, suggesting a role in resistance.
- Δ42PD-1+ T cells promoted HCC via toll-like receptors-4 signaling.
- Anti-Δ42PD-1 antibody, unlike nivolumab, inhibited tumor growth in murine HCC models.
Conclusions:
- Revealed Δ42PD-1 as a key mechanism of resistance to PD-1 ICB in HCC.
- Identified Δ42PD-1 as a potential therapeutic target for enhancing HCC immunotherapy.
