Scientists from A*STAR Genome Institute of Singapore (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 Cancer Cell 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."
