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Abstract
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.
- hepatocellular carcinoma
- immunotherapy
- T lymphocytes
- inflammation
- clinical trials
Data availability statement
The scRNA-seq data have been deposited in GEO under accession code GSE155736. Other data are available on reasonable request.
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Data availability statement
The scRNA-seq data have been deposited in GEO under accession code GSE155736. Other data are available on reasonable request.
Footnotes
Contributors ZC conceived and supervised the study. ZT and ZC designed the experiments, analyzed data and wrote the manuscript. KM coordinated clinical teams and experiments. ZT, MSC, DZ, CWY, KYK, YCW, XL and LL performed experiments. ZT, MY and Y-QS analyzed the scRNA-seq data. XY, TTC, YW, AW-HC, JZhou, KFT, JZhu, CML, AS-LC, SLC and KM provided HCC patients samples. KM and AS-LC provided critical comments and discussions.
Funding This work was undertaken with grant support from the Hong Kong Research Grant Council (TRS: T11-706/18-N, GRF: 17115818, 17104919 to ZC; TRS: T12-703/19-R to KM; GRF: 17121219 to TTC), the Hong Kong Health and Medical Research Fund (HMRF: 03142666, 04151266 and 05162326), University Development Fund and Li Ka Shing Faculty of Medicine Matching Fund from HKU to the AIDS Institute, and HKU Platform Technology Fund on Humanized Mice.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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