The Preventive Effect of the Phenotype of Tumour-Associated Macrophages, Regulated by CD39, on Colon Cancer in Mice

Abstract

Background: This study was designed to investigate the effect of cluster differentiation (CD)39 and CD73 inhibitors on the expresion of tumour-associated macrophages (TAMs), M1- versus M2-tumour phenotypes in mice with colon cancer. Methods: An in vivo study of co-culture with colon cancer cells and immune cells from the bone marrow (BM) of mice was performed. After the confirmation of the effect of polyoxotungstate (POM-1) as an inhibitor of CD39 on TAMs, the mice were randomly divided into a control group without POM-1 and a study group with POM-1, respectively, after subcutaneous injection of CT26 cells. On day 14 after the injection, the mice were sacrificed, and TAMs were evaluated using fluorescence-activated cell sorting. Results: In the in vivo study, the co-culture with POM-1 significantly increased the apoptosis of CT26 cells. The cell population from the co-culture with POM-1 showed significant increases in the expression of CD11b+ for myeloid cells, lymphocyte antigen 6 complex, locus C (Ly6C+) for monocytes, M1-tumour phenotypes from TAMs, and F4/80+ for macrophages. In the in vivo study, tumour growth in the study group with POM-1 was significantly limited, compared with the control group without POM-1. The expressions of Ly6C+ and major histocompatibility complex class II+ for M1-tumour phenotypes from TAMs on F4/80+ from the tumour tissue in the study group had significantly higher values compared with the control group. Conclusion: The inhibition of CD39 with POM-1 prevented the growth of colon cancer in mice, and it was associated with the increased expression of M1-tumour phenotypes from TAMs in the cancer tissue.

Docosahexaenoic acid may inhibit immune evasion of colorectal cancer cells through targeting immune checkpoint and immunomodulator genes and their controlling microRNAs

“…7 Park et al showed that administration of POT-1, the inhibitor of CD39, prevents colon cancer cells growth in mice and increases M1-phenotype macrophages in cancer tissue. 29 In present study, CD39 mRNA expression decreased after treatment with DHA, but its controlling miRNA, mir-142 increased in both HT-29 and Caco-2 cell lines. In this way, DHA through regulating CD39, may be effective in controlling CRC metastasis.…”

“…Künzli et al reported that survival duration in CRC tumors expressing a low level of CD39 was high and associated with less invasion 7 . Park et al showed that administration of POT‐1, the inhibitor of CD39, prevents colon cancer cells growth in mice and increases M1‐phenotype macrophages in cancer tissue 29 . In present study, CD39 mRNA expression decreased after treatment with DHA, but its controlling miRNA, mir‐142 increased in both HT‐29 and Caco‐2 cell lines.…”

Targeting immune checkpoints on tumor-associated macrophages in tumor immunotherapy

“…Both drugs are currently undergoing clinical trials (NCT03884556, NCT04306900, and NCT04261075). Polyoxotungstate, an inhibitor of CD39, has been shown to increase the levels of M1 anti-tumor macrophages as well as CD8 + T cells and significantly inhibit the growth of CT26 colon cancer ( 178 ). AB680, a selective CD73 inhibitor, induced the proliferation and cytotoxic activity of depleted CD8 + T cells and significantly inhibited the growth of colon cancer established by CT26 cells; moreover, it exhibited favorable pharmacokinetic properties.…”

Exploring the Expression of Adenosine Pathway-Related Markers CD73 and CD39 in Colorectal and Pancreatic Carcinomas Characterized by Multiplex Immunofluorescence: A Pilot Study

“…Immune checkpoint inhibitors have improved the treatment of cancer. However, many cancers do not respond to immunotherapy or develop resistance to therapy; therefore, efforts have been made to identify new targets and drugs that can improve the antitumor immune response [1][2][3][4][5].…”

“…CD39 is an ectoenzyme that degrades adenosine triphosphate and adenosine diphosphate into adenosine monophosphate [7,8]. CD73, expressed on the cell surface, degrades adenosine monophosphate into ADO [1][2][3].…”