《浸大讯》- 香港浸会大学校友事务处

校友王竣瑋博士（生物）以一級榮譽的成績於浸大畢業，並因其傑出的學術表現而獲得校內的學術獎。 受到祖父因癌症而去世的影響，他立志進行癌症治療的研究。在翁建霖教授的指導下，王校友在浸大的畢業論文集中於癌症免疫治療的研究。

畢業後，王校友繼續專注研究癌症治療，為加深對癌症免疫治療的認知，他於2019年透過香港卓越獎學金計劃，並在僅有百分之八的申請者入選的選拔下獲得獎學金，前往英國曼徹斯特大學深造， 其後在 Adam Hurlstone 博士的指導下於 2023 年完成癌症科學博士學位。 他在博士論文中探討如何透過一種名爲ADP-核糖基化酶14的蛋白質來逆轉對針對大腸癌、皮膚癌等癌症免疫療法的抗藥性。

王校友的研究成果更在癌症免疫治療的著名學術期刊《自然通訊》中發表。 此項肯定對王校友而言，只是他的研究生涯中的起點，他決心繼續進行癌症免疫療法的研究，期望造福更多癌症患者。

(訪問內容只供英文版本)

1. Please explain the mechanism of immunotherapy. Are all cancer patients suitable to receive immunotherapy?

Immunotherapy boosts our immune system to fight cancer. The immune system includes the lymph glands, spleen and white blood cells. Normally, it can spot and destroy faulty cells in the body, preventing cancer from further development. However, cancer might develop when the immune system recognises cancer cells but is not strong enough to kill them; or when cancer cells produce signals that stop the immune system from attacking them; or when cancer cells hide or escape from the immune system. There are different types of immunotherapies, including monoclonal antibodies, checkpoint inhibitors, vaccines, cytokines, and CAR-T cell therapy.

My doctoral study focused on the utilisation of checkpoint inhibitors. Checkpoint proteins are found on the surface of cells: PD-1 is found on the body’s T cells, and PD-L1 is found on normal cells. In general, PD-L1 binds with PD-1 to prevent T cells from being too strong which can destroy healthy cells in the body. However, cancer cells also present themselves as PD-L1 and therefore to ‘trick’ T cells by binding their PD-L1 with the T cells’ PD-1, avoiding recognition and preventing the T cells from killing them. Blocking the binding of PD-L1 to PD-1 with immune checkpoint inhibitors allows the T cells to recognise and kill cancer cells.

Each type of cancer is unique. Immunotherapy does not work for all types of cancer or for all people with cancer. However, doctors are continuing to try new treatments. Currently, immunotherapy has been proven to work in the following types of cancer: bladder, brain, breast, cervical, childhood, colorectal, esophageal, head and neck, kidney, leukemia, liver, lung, lymphoma and melanoma. In general, about 15 to 20% of cancer patients can overcome this disease by immunotherapy. However, there is still a majority of patients who do not yet benefit from it.

2. What is the difference between immunotherapy and other therapies in curing cancer?

Immunotherapy harnesses and enhances the natural powers of the immune system to work against disease by enabling the system to recognise, target and eliminate cancer cells throughout the body. It can be more targeted, selectively attacking cancer cells while minimising damage to healthy cells.

Other therapies like chemotherapy and radiation can destroy the DNA inside cells. This damage can stop them from growing. Our normal cells have a repair system to fix this damage, but cancer cells do not. As the damage builds up, these cancer cells keep trying to divide, and the damage eventually leads to their death. Generally, these treatments are less targeted and impact a wide range of rapidly dividing cells, which can lead to side effects.

3. How can your research findings contribute to current cancer therapy especially immunotherapy? How can cancer patients be benefited if your research findings are translated to practical application?

Interferon-gamma (IFNγ) is an immune mediator characterised as a paradoxical protein with both pro- and anti-tumor functions.  IFNγ can trigger processes in the body that directly kill cancer cells. However, IFNγ can also cause the body to produce molecules that slow down T-cells, which are the key components of the immune system to kill cancer cells.

Recently, as the first author, I published my findings in Nature Communications. The research revealed that exposure to chronic IFNγ conditions not only allows tumor cells to survive in the microenvironment but also induces a potent immunosuppressive microenvironment. Moreover, we identified a significantly upregulated enzyme, poly-ADP ribosyl polymerase 14 (PARP14), across human and mouse tumor cells treated with chronic IFNγ, inhibiting PARP14 reprograms tumor cells to exhibit a more immune-stimulatory phenotype, making them more likely to respond to PD-1 immunotherapy. In addition, PARP14 surprisingly can restrict T cells’ proinflammatory phenotype. Our work shows that stimulating T cells with a PARP14 inhibitor in long-term treatment results in T cells adopting a more proinflammatory phenotype, secreting more inflammatory cytokines which can kill cancer cells.

The discovery suggests that under tumor progression, tumor cells may undergo chronic IFNγ conditions, becoming resistant to immunotherapy. However, with PARP14 inhibitor intervention, the tumor microenvironment is completely reprogrammed, inducing T cells to produce more inflammatory cytokines, hence restricting tumor growth. This strategy can be combined with PD-1 immunotherapy to reinvigorate and strengthen anti-tumor immunity.

In this project, we teamed up with Ribon Therapeutics, Inc. (RTx), a biotech company that is working on creating new drugs to treat cancer and inflammation. Their approach involves targeting the emergency response systems inside cells that help them cope with stress. This collaboration uncovered that RTx’s PARP14 catalytic inhibitor (RBN012759) has a striking synergy with immunotherapy in the preclinical tumor models that we developed. The preclinical findings suggest that patients who progressed on immunotherapy might benefit from treatment with RTx’s PARP14 inhibitor.

Currently, at least 50% of cancer patients experience T cell exhaustion when treated with immunotherapy. This condition implies that T cells no longer secrete sufficient inflammatory cytokines, potentially leading to tumor recurrence and eventual mortality. This underscores the urgent need for a new target to rejuvenate T cell activity. My work demonstrates the significance of PARP14 in inhibiting T cell function in the anti-tumor response.

This work not only provides a key insight into how chronic IFN signaling in cancer cells drives immunotherapeutic resistance but also offers a new avenue for therapeutic targeting. Notably, drugs that inhibit PARP14 are currently in development. I believe my work would lay a solid foundation to test this new class of PARP14 inhibitors in clinical trials as an approach to reverse resistance and improve the overall efficacy of cancer immunotherapy.