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

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

Background

HCC is known to account 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 ICB cancer therapy by inhibition of negative immune regulation using antibodies targeting PD-1, such as Nivolumab. ICB therapy has led to prolonged survival and even cure in some cancer patients. ICB therapy, however, is not effective for approximately 80% of patients with HCC. Understanding the mechanism of the failed ICB, therefore, would be essential for discovering a new therapeutic target to save more lives of HCC patients.

Research methods and results

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

significance of the study

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

“We were the first research group to discover Δ42PD-1 protein in the world,” commented Professor Chen Zhiwei, director of the 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 activity of Δ42PD-1 on human T cells in both suppressing the antitumor immune response and promoting tumorigenesis, but also generate a potential anti-Δ42PD-1 antibody drug for the treatment of HCC”.

“In addition to immunotherapy against HCC, anti-Δ42PD-1 antibody can also be used as a drug to prevent HCC recurrence without inducing graft rejection after liver transplantation,” added Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed.

About the research group

The collaborative research team was led by Professor Chen Zhiwei, Director of the AIDS Institute and Professor, 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 in the 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 the 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 of the 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 of the Chinese University of Hong Kong.

Source:

The University of Hong Kong

Magazine reference:

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

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