A growing body of evidence has shown that people who regularly take aspirin have a lower risk for colorectal cancer (CRC) and are less likely to die if they do develop the disease.
The evidence surrounding aspirin and CRC is so intriguing that more than 70 000 people are currently participating in more than two dozen clinical studies worldwide, putting aspirin through its paces as an intervention in CRC.
A 2020 meta-analysis, for instance, found that 325mg of daily aspirin, the typical dose in a single tablet, conferred a 35% reduced risk of developing CRC, and a highly cited The Lancet study from 2010 found that a low dose of daily aspirin reduced the incidence of colon cancer by 24% and colon cancer deaths by 35% over 20 years.
But what, exactly, is aspirin doing?
We know that aspirin inhibits cyclooxygenase (COX) enzymes – COX-1 and COX-2, specifically – and that the COX-2 pathway is implicated in the development and progression of CRC, says Marco Scarpa, MD, PhD, staff surgeon at the University of Padova in Italy.
“However, the new thing we’ve found is that aspirin may have a direct role in enhancing immunosurveillance,” he told Medscape Medical News.
In April, Scarpa’s team published a paper in Cancer describing a mechanism that provides deeper insight into the aspirin-CRC connection.
Scarpa heads up the IMMUNOREACT study group, a collaboration of dozens of researchers across Italy running studies on immunosurveillance in rectal cancer.
In the baseline study, IMMUNOREACT 1, the team created and analysed a database of records from 238 patients who underwent surgery for CRC at the Azienda Ospedale Università di Padova from 2015 to 2019.
Using the same database, the latest findings from IMMUNOREACT 7 focused on the fate of the 31 patients (13%) who used aspirin regularly.
The researchers found that regular aspirin use did not appear to affect colorectal tumour stage at diagnosis, but tumour grading was significantly lower overall, especially in patients with BRAF mutations.
Regular aspirin users were also less likely to have nodal metastases and metastatic lymph nodes, and this effect was more pronounced in patients with proximal (right-sided) colon cancer vs distal (left-sided).
Most notably, IMMUNOREACT 7 revealed that aspirin has beneficial effects on the CRC immune microenvironment.
The team found that aspirin directly boosts the presence of antigens on gastrointestinal epithelial tumour cells, which can direct the body’s immune response to combat the cancer.
At a macro level, the aspirin users in the study were more likely to have high levels of tumour-infiltrating lymphocytes (TILs). Scarpa’s team had previously shown that high levels of CD8+ and CD3+ TILs were predictive of successful neoadjuvant therapy in rectal cancer.
Cytotoxic CD8+ T cells are central to the anticancer immune response, and in the latest study, a high ratio of CD8+/CD3+ T-cells was more common in aspirin users, suggesting a stronger presence of cancer-killing CD8+ cells. Expression of CD8 beta+, an activation marker of CD8+ cells, was also enhanced in aspirin users.
The most significant discovery, according to Scarpa, was that aspirin users were more likely to show high expression of CD80 on the surface of their rectal epithelial cells.
CD80 is a molecule that allows T cells to identify the tumour cell as foreign and kill it. Although cancer cells can down-regulate their CD80 to avoid detection by T cells, the study suggests that aspirin appears to help foil this strategy by boosting the production of CD80 on the surface of the tumour cells.
The researchers confirmed the clinical findings by showing that aspirin increased CD80 gene expression in lab-cultivated CRC cells.
“We didn’t expect the activation through CD80,” said Scarpa. “This means that aspirin can act on this very first interaction between the epithelial cell and the CD8+ lymphocyte.”
Overall, these new data suggest that aspirin helps activate the immune system, which helps explain its potential chemopreventive effect in CRC.
However, one puzzling result was that aspirin boosted expression of PD-L1 genes in the CRC cells, said Joanna Davies, DPhil, an immunologist who heads up the San Diego Biomedical Research Institute, California, and was not involved in the study.
PD-L1 serves as an “off” switch for patrolling T cells, which protects the tumour cell from being recognised.
“If aspirin is inducing PD-L1 on cancer cells, that is a potential problem,” said Davies. “An ideal therapy might be the combination of aspirin to enhance the CD8 T cells in the tumour and immune checkpoint blockade to block PD-L1.”
David Kerr, CBE, MD, DSc, agreed that high-dose aspirin plus immunotherapy might be “a wee bit more effective”. However, the combination would be blocked by the economics of drug development.
“Will anybody ever do a trial of 10 000 patients to prove that? Not on your nelly,” said Kerr, professor of cancer medicine at the University of Oxford, and regular Medscape contributor.
Despite the small patient numbers in the study, Kerr felt encouraged by the IMMUNOREACT analysis. “It’s a plausible piece of science and some quite promising work on the tumour immune microenvironment and the effects of aspirin on it,” he said.
Medscape article – How aspirin may lower risk for colorectal cancer (Open access)
See more from MedicalBrief archives:
Regular aspirin could lower colorectal cancer risk – US study
Pre-diagnosis aspirin use may lower colorectal cancer mortality — American Cancer Society