Study identifies Δ42PD-1 as novel therapeutic target for hepatocellular carcinoma immunotherapy

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HKUMed researchers at AIDS Institute, Department of Microbiology and Department of Surgery, School of Clinical Medicine, and School of Biomedical Sciences discover the role of an isoformic programmed cell death protein 1 (PD-1), namely Δ42PD-1, in suppressing the function of killer T cells, which is a type of immune cells essential for killing cancer cells among hepatocellular carcinoma (HCC) patients. The study is a breakthrough because it demonstrates that Δ42PD-1 causes stronger functional loss of killer T cells, revealing a molecular mechanism underlying the failure of PD-1-targeted immune checkpoint blockade (ICB) therapy. Moreover, antibody drug targeting at Δ42PD-1 inhibits HCC progression in animal models, which is independent of the PD-1 pathway. The full research article is now published online in the journal of Gut, a top-tier academic journal.

Background

It is well known that HCC accounts for up to 92.3% of liver cancer cases in China. The 2018 Nobel Prize in Physiology or Medicine was awarded for the discovery of cancer ICB therapy by inhibition of negative immune regulation using PD-1-targeted antibody, such as Nivolumab. The ICB therapy has resulted in prolonged survival and even cure in some cancer patients. The ICB therapy, however, is not effective for about 80% of HCC patients. Understanding the mechanism of unsuccessful ICB, therefore, would be essential for discovering a novel therapeutic target to save more lives of HCC patients.

Research methods and findings

The research team found that human T cells, which express Δ42PD-1 but not PD-1, account for up to 71% of killer T cells in untreated HCC patients. Δ42PD-1 positive T cells are mainly found in tumor tissues, associated significantly with HCC poor prognosis. Moreover, Δ42PD-1 positive T cells have weaker killing function than PD-1 positive T cells. Treatment of HCC patients using Nivolumab, the PD-1-targeted ICB drug, even increases the number of Δ42PD-1 positive T cells, especially in patients with tumor progression. We demonstrated that Δ42PD-1 positive T cells inside tumors promote HCC growth through activating toll-like receptors-4-mediated inflammation. Instead of Nivolumab, anti-Δ42PD-1 antibody inhibits tumor growth in three HCC/humanized murine models through blocking of the Δ42PD-1-TLR4 axis, reducing the number of Δ42PD-1 positive T cells and increasing functional killer T cells inside tumor. These findings not only revealed a mechanism underlying the unsuccessful PD-1-targeted ICB therapy but also identify Δ42PD-1 as a novel therapeutic target for HCC immunotherapy.

Significance of the study

This important discovery has provided scientific evidence that Δ42PD-1 may serve as a novel drug target against HCC or other relevant cancers and may warrant the clinical development of a humanized Δ42PD-1-specific antibody for immunotherapy against HCC and related human cancers/diseases.

'We were the first research group discovering the Δ42PD-1 protein in the world', commented by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, who led the study. 'In this study, we not only further discover the dual activities of Δ42PD-1 on human T cells in both suppressing anti-tumor immune response and promoting tumorigenesis but also generate a potential anti-Δ42PD-1 antibody drug for HCC treatment'.

'Besides immunotherapy against HCC, the anti-Δ42PD-1 antibody can also be used as a drug to prevent HCC recurrence without induction of graft rejection after liver transplantation', added by Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed.

About the research team

The collaborative research team was led by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, together with Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed and Dr Tan Zhiwu, research assistant professor at AIDS Institute and Department of Microbiology, School of Clinical Medicine, HKUMed. This collaborative team includes Chiu Mei-sum, Dr Zhou Dongyan, Yan Chi-wing, Kwan Ka-yi, Dr Wong Yik-chun, Li Xin, Dr Li Liu from AIDS Institute and Department of Microbiology, School of Clinical Medicine, HKUMed; Dr Yang Xinxiang, Dr Cheung Tan-to, Dr Wang Yuewen, Dr Zhu Jiye, Professor Lo Chung-mau, Department of Surgery, School of Clinical Medicine, HKUMed; Dr Yue Ming and Dr Song Youqiang from School of Biomedical Sciences, HKUMed; and Dr Anthony Chan Wing-hung, Dr Zhou Jingying, Professor To Ka-fai, Professor Alfred Cheng Sze-lok, Professor Stephen Lam Chan from the Chinese University of Hong Kong.

Source:
Journal reference:

Tan, Z., et al. (2022) Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients. Gut. doi.org/10.1136/gutjnl-2022-327133.

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