Despite successful treatment of early-stage cancer, many patients eventually develop metastatic recurrence due to the micro-metastases—small clusters of cancer cells—that may remain after primary therapy and later seed new tumors. Micro-metastases are susceptible to immune attack, lacking the immunosuppressive environment in large tumors. It opens up possibilities for preventive treatment that activates immunity and prevents recurrence in patients at risk of metastasis.
Meta-analyses of large randomized controlled trials have shown that regular aspirin use reduces the risk of metastasis and cancer-related mortality.
Aspirin is an irreversible inhibitor of cyclooxygenase (COX) enzymes. COX-1 is expressed in most tissues, including platelets, where it is essential for producing TXA2, a molecule involved in blood clotting. COX-2 is primarily activated during inflammation. Aspirin is rapidly eliminated from the body (within about 20 minutes), so frequent high doses are required to maintain COX-1 and COX-2 suppression in nucleated cells. However, even at low doses, aspirin effectively blocks COX-1 in platelets—cells without a nucleus that cannot resynthesize the enzyme once it is inhibited. As a result, low doses of aspirin reduce TXA2 levels.
Researchers at the University of Cambridge have shown that TXA2 regulates platelet function and suppresses anti-tumor immunity by limiting T-cell activity through ARHGEF1. By blocking TXA2 production, aspirin helps T cells more effectively combat micro-metastases.
ARHGEF1 Weakens T-cell Defense Against Metastases
Scientists have identified a protein that weakens immune protection against metastasis. In a previous genetic study on mice, the Arhgef1 gene was linked to more aggressive metastasis. Researchers compared normal mice with genetically modified mice lacking Arhgef1 to test its role. After injecting both groups with cancer cells, mice without ARHGEF1 had significantly fewer metastases in the lungs and liver.
The absence of ARHGEF1 did not affect the growth of primary tumors—only the spread of metastases. Scientists crossbred mice predisposed to metastatic breast cancer (BC) with Arhgef1-deficient mice, whose BC developed at the same rate as normal mice but had fewer metastases.
ARHGEF1 is predominantly expressed in hematopoietic cells. Its absence in these cells alone was sufficient to produce an anti-metastatic effect. In mice, ARHGEF1 deficiency activated genes associated with immune activation and tumor cell destruction.
ARHGEF1 has an immunosuppressive effect in T cells. Scientists selectively “switched off” Arhgef1 in various immune cells, including T cells, macrophages, and NK cells. Only removing ARHGEF1 in T cells reduced metastasis rates, confirming that ARHGEF1 weakens T-cell capacity to fight metastases.
ARHGEF1 Deficiency Improves T-cell Function
The ability of T cells to simultaneously produce multiple cytokines is a key feature of an effective antiviral and anti-tumor immune response. In Arhgef1-deficient mice, more T cells simultaneously expressed IFNγ, IL-2, and TNF.
Additionally, ARHGEF1-deficient T cells showed fewer signs of exhaustion—in which cells lose their ability to produce multiple cytokines and effectively fight tumors. Specifically, the expression of PD-1 and TOX, markers of exhausted T cells, was reduced.
The absence of ARHGEF1 did not affect early-stage metastasis formation (days 1-7 after tumor cell injection) but significantly limited metastasis at later stages (days 11-17). ARHGEF1 suppressed T-cell activity in cancer models and during bacterial infections, demonstrating its broader immunosuppressive role.
TXA2 Suppresses T Cells via ARHGEF1
T cells have 18 receptors that process external signals and regulate numerous cellular functions. Scientists tested whether ligands of these receptors could suppress T-cell activation through ARHGEF1. Most had no significant effect, but one—a synthetic analog of TXA2—strongly inhibited T-cell activation, and this effect was almost entirely ARHGEF1-dependent.
Wild-type T cells exhibited reduced proliferation and activation when T cells were exposed to the TXA2 analog, whereas ARHGEF1-deficient T cells remained active. Blocking the TXA2 receptor (TP) eliminated this effect. Suppression of T-cell proliferation and activation occurred independently of other immune cells, such as dendritic cells.
TXA2 signaling also inhibited the PI3K-AKT pathway, a critical regulator of T-cell activation, differentiation, and cytokine production. This suppression depended on ARHGEF1: activation of RHOA—a protein triggering inhibitory signaling—occurred only in T cells expressing ARHGEF1.
Thus, ARHGEF1 is essential for transmitting inhibitory signals from the TXA2 receptor, suppressing T-cell activation and proliferation in response to T-cell receptor (TCR) stimulation.
Aspirin Helps Combat Metastases by Freeing T Cells from TXA2 Suppression
COX inhibitors, including aspirin, block TXA2 biosynthesis. When mice were given a TXA2 analog in their drinking water, lung metastases increased. However, aspirin treatment reduced blood TXA2 levels and slowed metastasis—but only in mice with normal T cells. Aspirin had no effect in mice lacking ARHGEF1 in T cells, indicating that its action depends on the immune system. Aspirin enhanced T-cell activation to levels observed in ARHGEF1-deficient mice.
When aspirin-treated mice were also given a TXA2 analog, aspirin’s protective effect disappeared. However, in ARHGEF1-deficient mice, neither aspirin nor TXA2 influenced metastasis, confirming that aspirin inhibits metastasis by lowering TXA2 levels.
Platelet COX-1 Suppresses Anti-Metastatic Immunity
Aspirin’s anti-metastatic effect is linked to its impact on platelets. While aspirin inhibits COX-1 and COX-2, only COX-1 inhibition reduced metastases, accompanied by lower platelet-derived TXA2 levels.
When scientists selectively deleted COX-1 in platelets and their precursors, metastasis rates and TXA2 metabolite levels dropped. These findings indicate that aspirin and COX-1 inhibitors protect against metastasis by eliminating platelet-derived TXA2 suppression of T cells.
Conclusion
Platelets produce TXA2, suppressing T-cell immunity and promoting metastasis by activating ARHGEF1 in T-cells. ARHGEF1 inhibits T-cell anti-metastatic activity.
By inhibiting COX-1 in platelets, aspirin reduces TXA2 levels, freeing T cells from TXA2-mediated suppression and enhancing the anti-metastatic immune response.
Aspirin may serve as a valuable adjunct to immunotherapy for metastasis prevention. However, developing more selective drugs that specifically target the TXA2–ARHGEF1 pathway could further minimize side effects such as bleeding and gastric toxicity.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
Reference
Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity
