Like weary soldiers at the frontlines, the main fighters of our immune system—T cells— inevitably become exhausted from battling cancer cells in a harsh tumour microenvironment that blunts their attacks.
When T cells tire out, solid tumours such as breast and colon cancers get the opportunity to fight back and grow again. As a result, patients can end up not responding to immunotherapies, which work by galvanising immune cells to attack the tumours, or relapsing in the long run.
“Most research has focused on activating T cell killing capacity, but do not address prevention of T cell exhaustion and keeping T cells in a younger, more resilient state over time,” said Qiang Yu, a Senior Group Leader at the A*STAR Genome Institute of Singapore (A*STAR GIS).
In search of ways to minimise T cell exhaustion, Yu teamed up with colleagues from the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB); Nanyang Technological University and Tan Tock Seng Hospital in Singapore; University of Southern Denmark; and The Sixth Affiliated Hospital of Sun Yat-sen University, China.
By analysing tumour samples and genetic data from patients, the researchers found that high expression of a gene called P4HA1 was strongly associated with poor T cell formation and weaker responses to immunotherapy. The corresponding protein plays an important role in the energy system of T cells, and in cancers, pushes these immune cells toward exhaustion.
Graphical abstract of how P4HA1 induction promotes the differentiation of CD8+ T cells into exhausted cells in the microenvironments of solid tumours.
“The uniqueness of P4HA1 lies in its dual effect: blocking P4HA1 reduces T cell exhaustion and promotes the generation of long-lasting T cell progenitors, which are crucial for maintaining long-term anti-tumour immunity,” said Yu.
When the team inhibited P4HA1 in mice, T cells stayed active and healthy for a longer time, effectively shrinking the once-treatment-resistant tumours. Besides strengthening the immune response, P4HA1 inhibition also enhanced the effects of CAR-T cell immunotherapies by making these special T cells more effective at attacking the cancer cells.
Moreover, it could serve as a non-invasive biomarker, as high P4HA1 levels in the blood were found to be an early predictor of tumour relapse. According to Yu, a simple blood test might in the future be used to identify patients who are more or less likely to respond to immunotherapies, allowing for interventions like adding P4HA1 inhibitors in the treatment regimen.
Looking to translate their findings into clinically applicable solutions, the researchers are now developing P4HA1-targeting drugs that are effective and safe. “By targeting P4HA1 before or during treatment, we can reprogramme T cells to last longer and fight harder,” Yu said, envisioning that this strategy can improve the efficacy of existing immunotherapies and help overcome treatment resistance in solid tumours.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Genome Institute of Singapore (A*STAR GIS) and A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB).
