A new understanding of how aspirin stimulates the immune system to reduce the metastasis of some early cancers could lead to its targeted use to prevent some cancers from spreading, researchers report.
Writing in the journal Nature, the international research team led by the University of Cambridge explained that metastasising cancer cells were vulnerable to attack from the immune system as they were initially deprived of the immunosuppressive microenvironment within established tumours.
This unique vulnerability to immune attack was of interest to researchers seeking to find therapies that could take advantage of this weakness and prevent recurrence in patients with early cancer at risk of metastasis.
Aspirin was an agent of interest, with previous studies showing people with cancer who took daily low-dose aspirin had a reduction in the metastasis of some cancers, however the mechanism behind its anti-metastatic effect was unknown.
Limiting platelet TXA2 suppression of T-cell immunity
In this study, researchers were able to show cyclooxygenase 1 (COX-1) inhibitors, including aspirin, released T-cells from suppression by platelet-derived thromboxane A2 (TXA2), providing a mechanistic basis for aspirin’s anti-metastatic effect.
The discovery began with work to screen 810 genes in mice, with 15 shown to have effect on cancer metastasis and in particular mice lacking a gene that produced the protein Rho guanine nucleotide exchange factor 1 (ARHGEF1) having less metastasis of various primary cancers to the lungs and liver.
After showing that ARHGEF1 suppresses T-cells, the researchers were then able to determine that ARHGEF1 is switched on when T-cells are exposed to the clotting factor TXA2.
Aspirin was already known to reduce the production of TXA2, an action which leads to its to anti-clotting effects and gives it the ability to prevent cardiovascular events.
Given this, the researchers used a mouse model of melanoma to show that in mice who received aspirin, the frequency of metastases was reduced compared to control mice, and this action was dependent on releasing T-cells from suppression by TXA2.
‘Here we show that platelet-derived TXA2, functions as a potent immunoregulatory molecule that suppresses T-cell immunity to cancer metastasis by inducing the immunosuppressive function of ARHGEF1,’ the study authors wrote.
‘Consequently, COX-1 inhibition, including using aspirin, enhances anti-metastatic immunity by releasing T cells from TXA2- ARHGEF1-mediated suppression.’
The findings revealed a novel immunosuppressive pathway that limits T-cell immunity to cancer metastasis and provided mechanistic insights into the anti-metastatic activity of aspirin, potentially paving the way for more effective anti-metastatic immunotherapies, they concluded.
They noted that although aspirin provided a potentially attractive opportunity for anti-metastatic therapy given its low cost, more selective targeting of the TXA2-ARHGEF1 pathway could enable enhanced anti-metastatic activity and/or reduced bleeding risk and gastric toxicity.
‘A unique therapeutic window of opportunity’
Study senior author Professor Rahul Roychoudhuri, professor of cancer immunology in the Department of Pathology at the University of Cambridge, said many patients with early-stage cancers received potentially curative treatment, but later relapsed due to the eventual growth of micrometastases.
‘Most immunotherapies are developed to treat patients with established metastatic cancer, but when cancer first spreads there’s a unique therapeutic window of opportunity when cancer cells are particularly vulnerable to immune attack,’ he said.
‘We hope that therapies that target this window of vulnerability will have tremendous scope in preventing recurrence in patients with early cancer at risk of recurrence.’
Study first author Dr Jie Yang, senior research associate in the Department of Pathology at the University of Cambridge, said it was a ‘Eureka moment’ when the research team discovered TXA2 was the molecular signal that activated the suppressive effect on T-cells.
‘Before this, we had not been aware of the implication of our findings in understanding the anti-metastatic activity of aspirin,’ Dr Yang said.
‘It was an entirely unexpected finding which sent us down quite a different path of enquiry than we had anticipated.’
Collaboration with the Add-Aspirin trial
The researchers plan to help the translation of their work into potential clinical practice by collaborating with Professor Ruth Langley, professor of oncology and clinical trials at the MRC Clinical Trials Unit at University College London, who is leading the Add-Aspirin clinical trial.
Together, they will work to find out if aspirin can stop or delay early-stage cancers from returning.
Professor Langley commented: ‘This is an important discovery. It will enable us to interpret the results of ongoing clinical trials and work out who is most likely to benefit from aspirin after a cancer diagnosis.’
