Checkpoint inhibitor immunotherapies, such as PD-1 blockade, fail to provide sufficient protection in patients with liver metastasis. Source: GEN Genetic Engineering & Biotechnology News

T-cell protein, a step forward in liver cancer immunotherapy

9 December 2022

Researchers at the University of Hong Kong reveal why a molecular mechanism in immune checkpoint blockade therapy has been unsuccessful against hepatocellular carcinoma while also locating a novel target in the fight against liver cancer.

In 2018, the Nobel Prize in Physiology or Medicine was awarded to Dr James P. Allison and Dr Tasuku Honjo for developing a new approach to cancer therapy – i.e., identifying the mechanisms that inhibit the immune system from attacking cancer. The two Laureate’s parallel discoveries have ushered in what is known as the “immune checkpoint blockade” therapy along with a whole class of drugs that deploy one's own immune system to attack tumour cells. The results are prolonged survival and even cure in some cancer patients.

To date, checkpoint inhibitor immunotherapies have been ineffective for about 80% of patients with hepatocellular carcinoma, the most common type of liver cancer, accounting for as much as 92.3% of cases in China. Researchers at the University of Hong Kong intended to understand why these cancer therapies are unsuccessful against hepatocellular carcinoma, and in their study found a novel target against hepatocellular carcinoma.

The team led by Professor Chen Zhiwei studied the immune cell protein PD-1, discovered by Honjo, and its isoform. Specifically, the researchers were trying to find the role this isoformic programmed cell death protein has in suppressing killer-T-cell function, which are essential for destroying cancer cells. Demonstrating that this protein, called Δ42PD-1, causes stronger functional loss of killer T cells, the team revealed a molecular mechanism underlying the failure of earlier therapy targeted at PD-1. They also identified Δ42PD-1 as a novel therapeutic target in immunotherapy for hepatocellular carcinoma. The full research article is now published online in the journal of Gut.

“We were the first research group discovering the Δ42PD-1 protein in the world.” said Chen, Director of AIDS Institute and Professor of the Department of Microbiology at the Hong Kong University medical school. “In this study, we not only further discover the dual activities of Δ42PD-1 on human T cells in both suppressing anti-tumour immune response and promoting tumorigenesis but also generate a potential anti-Δ42PD-1 antibody drug for [hepatocellular carcinoma] treatment.”