Metastasis, the spread of cancer cells from primary tumors to distant organs, is the cause of 90% of cancer deaths worldwide. The immune system plays a significant role in fighting metastasis, but cancer cells often find ways to evade immune surveillance, ultimately leading to this biological phenomenon that remains a top priority in cancer research. It is said that it is not the primary tumor that leads to mortality but the metastasis.
Research on metastasis is robust, numerous, and focused on all areas related to its occurrence and development, where evasion of immune surveillance is the main starting point. One of these evasion methods involves the production of thromboxane A2 (TXA2) by blood platelets, which suppresses the activity of T cells, a type of immune cell, at metastatic sites. This suppression hinders the immune system's ability to effectively attack and eliminate cancer cells in metastasis.
Now, a new international analysis coordinated from the University of Cambridge in the United Kingdom has found that aspirin is capable of reducing the occurrence of metastasis in mice by allowing the activation of T lymphocytes capable of recognizing tumor cells.
The research, published in Nature, observed that different mouse cancer models - including breast, colon, and melanoma - treated with aspirin showed a lower rate of metastasis in other organs such as the lungs and liver compared to untreated mice. "The finding, according to the authors, opens new avenues for the use of more effective anti-metastasis immunotherapies."
Aspirin has previously been associated with a reduction in metastasis in some organs, but the precise mechanism of action is unclear. The British team, coordinated by Rahul Roy Choudhuri from the Department of Pathology at the aforementioned university, conducted experiments in a mouse model where they found a new immunosuppressive pathway targeted by aspirin to enhance anti-metastatic immunity. Thus, various different mouse cancer models, including breast cancer, melanoma, and colon cancer, treated with aspirin exhibited a lower rate of metastasis in other organs such as the lungs and liver compared to untreated control mice.
The article notes that aspirin is known to inhibit cyclooxygenase 1 - an enzyme involved in inflammation - in platelets and reduce TXA2 production. "It has been observed that this reduction in TXA2 alleviates T cell suppression, thus enhancing their ability to combat metastatic cancer cells," the authors indicate.
Complementary Therapy and Combined Future
According to Roy Choudhuri, these findings suggest that aspirin could be used as a relatively inexpensive, low-tech, and effective complementary therapy to prevent cancer metastasis by stimulating the natural immune response in mice. Future research could explore the combination of aspirin with other immunotherapies to further enhance its anti-metastatic effects, as highlighted in the study, which also emphasizes the interest in therapeutically exploiting this immunological vulnerability to prevent recurrence in early-stage cancer patients at risk of metastasis.
The study demonstrates that cyclooxygenase 1 (COX-1) inhibitors, including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A2 (TXA2). TXA2 acts on T cells to activate an immunosuppressive pathway dependent on ARHGEF1 guanine exchange factor, suppressing signaling, proliferation, and effector functions of receptor-driven T cells. "Conditional specific deletion of T cell Arhgef1 in mice increases T cell activation at the metastatic site, leading to immune-mediated rejection of pulmonary and hepatic metastases.
Consequently, and according to the study coordinator, "restricting TXA2 availability through aspirin, selective COX-1 inhibitors, or specific platelet deletion of COX-1 reduces the metastasis rate in a manner dependent on intrinsic T cell expression of ARHGEF1 and TXA2 signaling 'in vivo'." These findings, he continues, reveal a new immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.
Although aspirin offers a potentially attractive opportunity for anti-metastatic therapy due to its low cost, a more selective targeting of the TXA2-ARHGEF1 pathway could allow for improved anti-metastatic activity and/or reduced risk of bleeding and gastric toxicity. Understanding the immunostimulatory effect of aspirin raises the possibility that this molecule could be used to create synergy with other adjuvant immunotherapies.
The results are based on previous data showing that in colon cancer patients, the association of aspirin use with better survival seems to be restricted to cancers with high expression of HLA class I9, suggesting that other immunological biomarkers may help stratify patients who are more likely to benefit from aspirin's anti-metastatic activity.
Given the contradictory evidence regarding the efficacy of aspirin in different patient groups, the data underscore, according to the authors, the need for detailed studies of biomarker identification in the context of prospective randomized controlled trials to definitively establish the types of cancer and patient populations in which aspirin is most effective.