![]() ![]() Studies have revealed that cholesterol metabolism is closely related to the change of macrophage polarization 13. It is now well-established that M1-like macrophages are pro-inflammatory and anti-tumor, while M2-like macrophages are anti-inflammatory and pro-tumor 12. ![]() Macrophages are ideally divided into two types in vitro, namely, M1-like macrophages and M2-like macrophages. Macrophages, which account for the largest number of tumor interstitial cells, play important roles in regulating adaptive immunity and tumor progression. However, how the tumor immune microenvironment is regulated by 5Aza is still not fully elucidated. also found that 5Aza could enhance the activity of CD8 + T cells and inhibit tumor growth 11. Therefore, DNA methylation inhibitors combined with immunotherapy have been applied in the treatment of cancers and achieved remarkable outcomes 9, 10. As indicated by previous studies, 5Aza can activate the immune response against tumors by stimulating the expression of endogenous retroviruses or immunosurveillance related genes in tumor cell 8, 9. However, because the effects of 5Aza are varied, the underlying mechanisms are still not fully understood. Initially, researchers found that 5Aza can kill tumor cells by reactivating genes that had been silenced by methylation, which control cell growth 7. 5-aza-2'-deoxycytidine (5Aza), a previously identified DNA methyltransferase (DNMT) inhibitor, has been approved by FDA for the treatment of myelodysplastic syndrome. In recent years, DNA methylation inhibitors in cancer therapy has achieved remarkable efficacy. The development of new therapies for CRC-PC is urgently needed. However, the treatment of CRC-PC has stagnated in the past decade. As the current primary treatment for CRC-PC, complete surgical resection and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved 5-year survival outcomes in these patients by up to 40-45% 5, 6. Compared with a median survival of 18.1 months in CRC patients without PC, patients with CRC-PC had a median survival of only 6.7 months, which was considered to be in the terminal phase 4. In addition to the hematogenous and lymphatic routes, CRC usually gives rise to transcoelomic spread (especially after surgery) and ultimately causes peritoneal carcinomatosis (PC) 2, 3. Finally, we validated the reprogramming role of 5Aza in antitumor immunity in stromal macrophages and T cells from CRC patients.Ĭonclusions: Taken together, our findings showed for the first time that 5Aza suppressed CRC-PC by regulating macrophage-dependent T cell activation in premetastatic microenvironment, meanwhile uncovered a DNA methylation-independent mechanism of 5Aza in regulating ABC A9-associated cholesterol metabolism and macrophage activation.Īs the third common malignant tumor, colorectal cancer (CRC) is a serious threat to human health 1. In addition, the antitumor effect of 5Aza was synergistically potentiated by conventional chemotherapeutic drugs 5-Fu or OXP. ![]() Pharmacological inhibition of NF-κB, or genetic depletion of IL-6 abolished the antitumor effect of 5Aza in mice. 5Aza induced cholesterol accumulation, p65 phosphorylation and IL-6 expression in an ABC A9-dependent manner. Furthermore, we screened and identified ATP-binding cassette transporter A9 (ABC A9) as a binding target of 5Aza. Mechanistically, 5Aza stimulated primary mouse macrophages toward to a M1-like phenotype characterized by the increase of p65 phosphorylation and IL-6 expression. Results: 5Aza could stimulate the activation of macrophages toward an M1-like phenotype and subsequent activation of T cells in premetastatic fat tissues, and ultimately suppress CRC-PC in immune-competent mouse models. The effects of 5Aza on tumor immunity were validated in stromal macrophages and T cells from CRC patients. The effects of 5Aza on macrophage activation were studied by flow cytometry, real-time PCR, Western blotting assays, and Drug Affinity Responsive Target Stability (DARTS). Methods: The role of 5Aza in immune microenvironment of peritoneal carcinomatosis (PC) of colorectal cancer (CRC) was investigated. However, the molecular mechanisms by which 5Aza regulates tumor immune microenvironment are still not fully understood. Background: 5-aza-2'-deoxycytidine (5Aza), a DNA methyltransferase (DNMT) inhibitor, could activate tumor adaptive immunity to inhibit tumor progression. ![]()
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