Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion

Area of Science:

• Oncology
• Immunology
• Cancer Chemoprevention

Background:

• Selective cyclooxygenase-2 (COX-2) inhibitors show chemopreventive effects against various cancers.
• The precise mechanisms underlying COX-2 inhibitor-mediated cancer prevention remain incompletely understood.
• Immune cell populations, particularly myeloid-derived suppressor cells, play a critical role in tumor progression.

Purpose of the Study:

• To investigate the impact of the selective COX-2 inhibitor, celecoxib, on immature myeloid suppressor cells (IMSCs) during intestinal tumor chemoprevention.
• To elucidate the effects of celecoxib on immune cell dynamics and associated molecular pathways in a mouse model of colon carcinogenesis.
• To explore the potential of celecoxib in modulating the tumor microenvironment and immune surveillance.

Main Methods:

• Administration of celecoxib to Swiss mice during 1,2-dimethylhydrazine dihydrochloride (1,2-DMH) induced intestinal tumorigenesis.
• Flow cytometric analysis to quantify Gr1(+)CD11b(+) immature myeloid suppressor cells (IMSCs) and lymphocyte populations (T cells).
• Quantitative reverse transcription polymerase chain reaction (RT-qPCR) to assess messenger RNA (mRNA) levels of inducible nitric oxide synthase (NOS-2) and arginase (Arg) in splenic tissue.

Main Results:

• Celecoxib treatment significantly reduced the number of IMSCs in mice with 1,2-DMH-induced intestinal tumors.
• Celecoxib administration increased splenic lymphocyte numbers and enhanced lymphocyte infiltration into tumors.
• Tumor development was associated with increased IMSCs and decreased splenic T cell number and function, which were reversed by celecoxib.
• Celecoxib normalized elevated mRNA levels of NOS-2 and Arg in the spleen of tumor-bearing mice.
• Celecoxib therapy delayed tumor induction, reduced tumor incidence, and reversed CD4(+) T cell loss.

Conclusions:

• Celecoxib, a selective COX-2 inhibitor, effectively suppresses intestinal tumorigenesis in mice.
• Celecoxib exerts its chemopreventive effects, in part, by modulating the frequency of IMSCs and enhancing anti-tumor T cell responses.
• The findings suggest that celecoxib's regulation of IMSCs and CD4(+) T cells contributes to its efficacy in preventing autochthonous intestinal tumors.