Long-term daily use of aspirin can help to prevent the development and progression of colorectal cancer (CRC) but the mechanisms involved have been unclear. New research headed by investigators at the University of Padova, has revealed that aspirin may exert these protective effects by boosting certain aspects of the body’s immune response against cancer cells. The team, headed by Marco Scarpa MD, PhD, of the University of Padova, analyzed clinical and pathological data from patients who had undergone surgery for their CRC, and also carried out studies using CRC cell lines. Reporting their findings in Cancer, in a paper titled “IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer,” the team noted that their results suggest that “regular aspirin use may have an active role in enhancing immunosurveillance against CRC.”

Colorectal cancer (CRC) is the third most common cancer and the fourth most frequent cause of cancer deaths worldwide, the authors noted. Several studies have demonstrated that aspirin—a nonsteroidal anti-inflammatory drug (NSAID)—can play an important role in the chemoprevention of CRC, and a recent meta-analysis of 45 studies concluded that regular aspirin use is associated with a significantly reduced risk of CRC onset, they noted. “In fact, many long‐term follow‐ups of randomized controlled trials of aspirin versus control have shown that daily aspirin use reduces incidence and mortality from CRC, after a latent period of approximately 8 to 10 years …”

However, the underlying mechanisms by which aspirin can prevent CRC are not well understood. “The inhibition enzymes that perpetuate proinflammatory signals, such as prostaglandin‐endoperoxide synthase 1 and COX‐2 (prostaglandin-endoperoxide synthase 2), are considered the main chemopreventive mechanisms in aspirin users,” the authors noted. “However, previously studies have shown that besides the “classical inhibition of the carcinogenetic COX-2 pathway,” regular use of aspirin is associated with an increase of tumor-infiltrating lymphocytes (TILs), “… and the implication of these observations is potentially crucial to increase the effect of immunotherapy or to enhance the effect of standard chemotherapy.”

To investigate the effects of aspirin on colorectal cancer, the researchers obtained tissue samples from 238 patients who underwent surgery for colorectal cancer in 2015–2019. Of these, 12% were aspirin users. Patients were enrolled in the METACCRE section of the IMMUNOlogical microenvironment in the REctal Adenocarcinoma Treatment (IMMUNOREACT 7) multicenter observational study. The study was mainly carried out at the University Hospital of Padova.

The analyses showed that, compared with tissue samples from patients who did not use aspirin, samples from aspirin users showed less cancer spread to the lymph nodes and higher infiltration of immune cells into tumors. As part of their study the team looked at the neutrophil to lymphocyte (NLR) ratio in study patients. “To assess the effect of regular aspirin, use on the systemic immune response to CRC, we analyzed the neutrophil to lymphocyte ratio (NLR) in the METACCRE cohort,” they explained. “NLR is known as a simple, cheap, and easily accessible biomarker that has a potential role in the prediction of CRC outcomes.” They found that this NLR measure was “significantly lower in aspirin users,” suggesting a better oncological prognosis in regular aspirin users, compared with nonusers. Reporting on this finding, the team said, “We hypothesize that the low NLR (meaning high circulating lymphocytes and low circulating neutrophils) observed in our patients is the systemic reflex of a more favorable tumor microenvironment observed in aspirin‐using patients.”

The team’s analyses of colorectal cancer cells in the lab also showed that exposing the cells to aspirin caused increased expression of a protein called CD80 on certain immune cells, which enhanced the capacity of the cells to alert other immune cells of the presence of tumor-associated proteins. Supporting this finding, the researchers found that in patients with rectal cancer, aspirin users had higher CD80 expression in healthy rectal tissue, suggesting a pro-immune surveillance effect of aspirin. They also carried out tests in cell lines. “ … in silico data from an external cohort and our in vitro experiment showed that aspirin treatment of CRC cells can upregulate the expression of CD80, enhancing the capacity of these cells to actively present tumor antigens to T cells.”

Reporting on their collective studies, the team stated, “In conclusion, our data suggested that aspirin use may be associated with a lower grading and nodal metastasis rate and a higher TILS infiltration in patients with CRC … Our data might strengthen the hypothesis that the mere pharmacological inhibition of COX, mediated by aspirin can enhance the TILs infiltration within the tumor microenvironment.”

Scarpa further noted, “Our study shows a complementary mechanism of cancer prevention or therapy with aspirin besides its classical drug mechanism involving inhibition of inflammation. Aspirin is absorbed in the colon by passive diffusion to a significant degree. Its absorption is linear and depends on concentration along the bowel, and in the rectum, the concentration of orally administered aspirin can be much lower than in the rest of the colon. Thus, if we want to take advantage of its effects against colorectal cancer, we should think of how to guarantee that aspirin reaches the colorectal tract in adequate doses to be effective.”

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