The mechanism of Aspirin regulation of immune and anti-cancer
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The mechanism of Aspirin regulation of immune and anti-cancer
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The mechanism of Aspirin regulation of immune and anti-cancer
“Science Advances”: The mechanism of aspirin’s regulation of immune and anti-cancer has been clarified! Scientists find that aspirin increases levels of pro-inflammatory mediators, reprograms
The preventive effect of the first-generation “magic drug” aspirin in cancer has been verified in many studies, among which colorectal cancer (CRC) has the most significant effect. Recommended drugs for CRC prevention in people at cardiovascular risk. However, at present, the mechanism by which aspirin regulates immunity is not very clear.
A recent study in the journal Science Advances [1] just revealed the answer.
The researchers found that aspirin can act in multiple ways to limit the progression of inflammatory CRC.
It reduces proto-oncogene expression, increases levels of specific pro-inflammatory resolution mediators (SPMs), including lipoxin A4 and resolvin D1, etc., reprograms macrophages to a protective phenotype, reduces macrophage Expression of the immunosuppressive receptor PD-1 in cells and colonic mucosal CD8+ T cells.
Previous studies have shown that aspirin, as a cyclooxygenase (COX) inhibitor, can be acetylated and modified to inhibit the production of prostaglandins and thromboxane.
Prostaglandin E2 can inhibit host immunity and promote tumor growth [2], And thromboxane A2 can promote tumor metastasis in a platelet-dependent way [3].
However, increasing evidence suggests that these mechanisms alone are not sufficient to explain the immunomodulatory effects of aspirin in CRC.
The enzymatic activity is inhibited upon acetylation of COX-1, whereas the enzymatic activity is retained upon acetylation of COX-2, and its catalytic activity is transferred to promote the production of a protective molecule, aspirin-activated SPM (AT-SPM). [4,5].
Moreover, studies have shown that people with high COX-2 expression levels regularly take aspirin to reduce the risk of CRC more significantly than those with low COX-2 levels [6].
Therefore, the researchers focused this study on SPM.
They selected the AOM/DSS-induced inflammatory bowel cancer mouse model, and first determined the appropriate aspirin dose.
The experiment showed that the moderate dose of 43mg/kg (equivalent to the human dose of 325mg/day) had the greatest protective effect, It can effectively inhibit inflammation, prevent the shortening of the colon caused by inflammation, and reduce the area of intestinal polyps.
Colon length and polyp area comparison between aspirin group (ASA) and control group
At the same time, the expression of proto-oncogene c-myc, trefoil factor 3 (Tff3) and triose phosphate isomerase 1 (Tpi1) involved in cellular glycolysis in the colorectal tissue of mice taking aspirin decreased compared with those taking placebo.
The number of ki67-positive cells was significantly reduced. Correspondingly, the expression of the tumor suppressor gene Pten increased.
At this dose, there were significant reductions in colonic tissue levels of all intermediates in the glycolytic pathway, most of which were statistically significant, such as dihydroxyacetone phosphate and lactate.
Increased glycolysis is a typical metabolic change in CRC and is thought to be responsible for part of the immunosuppressive pathway.
There were also significant changes in immune cells. First, there is a decrease in the number of lamina propria macrophages and changes in the cellular phenotype , and this phenotypic change is associated with increased expression of the chemokine receptor CX3CR1, which is also associated with improved prognosis in inflammatory CRC [7].
Multivariate analysis of the lipid mediator profiles of macrophages revealed increased levels of several SPMs, including lipoxin A4 and resolvin D1, suggesting that aspirin directly modulates macrophage phenotype and function, converting them Reprogrammed to a protective phenotype.
Expression analysis of macrophage phenotypic markers in aspirin group mice (ASA) and control groups showed significant separation
At the same time, the expression of the immunosuppressive receptor PD-1 in macrophages was also significantly reduced, which improved the phagocytosis rate and number of apoptotic cells by macrophages.
In addition to macrophages, aspirin also affected the phenotype and function of different types of T cells.
As the core force of identifying and killing cancer cells, CD8+ T cells are also the main target of cancer cells.
Aspirin reduces the expression level of PD-1 on each CD8+ T cell, and also reduces the CD8+ T cells expressing PD-1.
Quantitatively, reductions in PD-1 were significantly associated with increased levels of the effector cytokine interferon gamma.
In immunosuppressive CD4+ T cells, the levels of the proinflammatory cytokine interleukin-17 were significantly reduced. In human CD8+ T cells, the researchers found the same changes.
These changes in tissue metabolism and immune cell phenotype and function are based on changes in SPM levels .
In the colon tissue of aspirin-treated mice, the researchers detected acetylated COX-2, lipoxins A4, B4 and Levels of resolvin D1 and D3 also increased with treatment time , reaching a peak after one week, and this increase cooperated with a decrease in the immunosuppressive mediators prostaglandins E2, D2, and thromboxane A2, mediating the effect of aspirin in inflammatory conditions. Protection in CRC.
Changes in the levels of resolvin D1, D3 and lipoxin A4 , B4 with time (starting from AOM/DSS induction) in aspirin group (ASA) and control group
Lipoxin A4 and resolvin D1, D3 have cognate receptors Alx/Fpr2 receptors, in mice lacking Alx/Fpr2 receptors, polyp area, macrophage phenotype, and PD-1 expression even after aspirin , CD8+ T cell PD-1 expression, and disease severity were not different from placebo treatment.
Likewise, pharmacological inhibition of SPM synthesis would also negate the protective effect of aspirin. Direct treatment of mice with a 15 ng dose of the SPM mixture resulted in protection similar to aspirin treatment.
This suggests that aspirin indeed modifies the phenotype, function and/or PD-1 expression levels of macrophages, CD8+ T cells and CD4+ T cells by acetylating COX-2, increasing SPM levels, binding to Alx/Fpr2 receptors , plays a protective role in inflammatory bowel cancer.
The researchers believe that this study identifies a previously underappreciated mechanism of aspirin’s prevention of CRC, which could be used to develop immune reprogramming therapies to treat CRC, and that, in future studies, SPM could be used to assess the efficacy of aspirin in preventing inflammatory CRC. a potential biomarker [8].
references:
[1] De Matteis R, Flak M B, Gonzalez-Nunez M, et al. Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer[J]. Science Advances, 2022, 8(5): eabl5420.
[2] Zelenay S, Van Der Veen A G, Böttcher J P, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity[J]. Cell, 2015, 162(6): 1257-1270.
[3] Lucotti S, Cerutti C, Soyer M, et al. Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A 2[J]. The Journal of clinical investigation, 2019, 129(5): 1845-1862.
[4] Serhan C N, Hong S, Gronert K, et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals[J]. The Journal of experimental medicine, 2002, 196(8): 1025-1037.
[5] Claria J, Serhan C N. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions[J]. Proceedings of the National Academy of Sciences, 1995, 92(21): 9475-9479.
[6] Chan A T, Ogino S, Fuchs C S. Aspirin use and survival after diagnosis of colorectal cancer[J]. Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al. Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevents carcinogenesis[J]. Cancer research, 2017, 77(16): 4472-4485.
[8] https://www.qmul.ac.uk/whri/news-and-events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.html
The mechanism of aspirin regulation of immune and anti-cancer
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