òòò½Íø

17 January 2025

Targeting P4HA1 enhances CD8 T cell progenitor expansion, fostering systemic anti-tumour immunity to achieve long-term tumour control (Source: Ma S, et.al, Cancer Cell, 2024)

L-R: Jiang Zemin, Ong Li Teng, Yu Qiang, Ma Shijun

Singapore – Scientists from A*STAR Genome Institute of òòò½Íø(A*STAR GIS) have uncovered that a key enzyme – P4HA1 prolyl hydroxylase, is strongly induced in CD8+ T cells in solid cancer, the primary immune cells involved in combating cancer. P4HA1 causes disruptions in energy production within the cells, which leads to weaker immune cells that are less able to fight cancer and form long-lasting anti-cancer immunity, highlighting P4HA1 as a promising target for treating solid tumours.

By inhibiting P4HA1 with small molecule compound, researchers were able to restore healthy immune cell function and sustain long term immune memory, helping to shrink tumours and prevent tumour relapse. Notably, targeting P4HA1 demonstrated significant efficacy in immune resistant tumours in mouse models. In addition to improving natural immune responses, targeting P4HA1 could also enhance CAR-T cell therapy, a specialized cancer treatment, by making the modified immune cells stronger and more effective. Their discovery was recently published in in December 2024.

The study also revealed that P4HA1 levels in the blood immune cells increase with cancer progression and relapse, and correlate with patients' responses to immunotherapies. This highlights P4HA1 not only as a promising target to enhance the immune system’s ability to fight cancer, paving the way for effective and long-lasting cancer therapies, but also making it a potential biomarker for monitoring tumour recurrence and immunotherapy outcomes.

While many metabolic and epigenetic regulators involved in T cell fate are consistently expressed at high levels, playing indispensable roles in normal T cell functions, they are challenging to target specifically for anti-tumour therapies. In contrast, P4HA1 is expressed at low basal levels in naïve and memory T cells, becoming significantly upregulated upon T cell activation and further enriched in exhausted T cells within the tumour microenvironment (TME). This makes P4HA1 a highly selective target for activated and exhausted T cells and a promising biomarker for cancer monitoring.

Their research highlights the importance of systemic immunity in anti-cancer responses. By studying tumour-draining lymph nodes (TDLNs) and peripheral blood, the researchers demonstrated that targeting P4HA1 in immune cells not only enhances systemic immune responses but also sustains them over time, leading to prolonged tumour control and improved therapeutic outcomes.

Prof YU Qiang, Senior Group Leader, Laboratory of Precision Cancer Medicine at A*STAR GIS, who led this research, shared, “Our work bridges fundamental science and clinical applications. Based on this discovery, we are committed to developing optimized P4HA1-targeting strategies, including chemical inhibitors and next-generation CAR-T cell platforms, to deliver efficient and feasible treatment technologies and solutions for improved treatment for solid tumours.”

 Dr WAN Yue, Executive Director, A*STAR GIS, commented, “The findings on the potential of P4HA1 as a peripheral biomarker for cancer progression and immunotherapy resistance could enable more precise monitoring and personalized treatment strategies in future, improving immunotherapy outcomes and further advancing patient safety and care.”

For media queries and clarifications, please contact:

Eliza Lim (Ms)
Senior Manager, Office of Corporate Communication
A*STAR’s Genome Institute of òòò½Íø(GIS)
Email: Eliza_Lim@gis.a-star.edu.sg

òòò½Íø’s Genome Institute of òòò½Íø(GIS)

The Genome Institute of òòò½Íø(GIS) is an institute of the òòò½Íø, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, the GIS pursues the integration of technology, genetics, and biology towards academic, economic and societal impact, with a mission to "read, reveal and (ω)rite DNA for a better òòò½Íøand world".

Key research areas at the GIS include Precision Medicine & Population Genomics, Genome Informatics, Spatial & Single Cell Systems, Epigenetic & Epitranscriptomic Regulation, Genome Architecture & Design, and Sequencing Platforms. The genomics infrastructure at the GIS is also utilised to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.

For more information about GIS, please visit www.a-star.edu.sg/gis.

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About the òòò½Íø, Technology and Research (A*STAR)

The òòò½Íø, Technology and Research (A*STAR) is Singapore's lead public sector R&D agency. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit the economy and society. As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by improving societal outcomes in healthcare, urban living, and sustainability. A*STAR plays a key role in nurturing scientific talent and leaders for the wider research community and industry. A*STAR’s R&D activities span biomedical sciences to physical sciences and engineering, with research entities primarily located in Biopolis and Fusionopolis. For ongoing news, visit www.a-star.edu.sg.

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