5-Fluorouracil Suppresses Colon Tumor through Activating the p53-Fas Pathway to Sensitize Myeloid-Derived Suppressor Cells to FasL + Cytotoxic T Lymphocyte Cytotoxicity

• Published in: Cancers 2023-03, Vol.15 (5), p.1563
• Main Authors: Yang, Yingcui, Zhang, Mingqing, Zhang, Yongdan, Liu, Kebin, Lu, Chunwan
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Antibodies; Apoptosis; Cancer; Cancer therapies; Cell activation; Cell death; Cell survival; Chemotherapy; Cloning; Colon cancer; Colorectal cancer; Colorectal carcinoma; Cytokine receptors; Cytotoxicity; Dosage and administration; Drug therapy; FasL protein; Flow cytometry; Fluorouracil; Health aspects; Homeostasis; Infiltration; Ligands; Lymphocytes; Lymphocytes T; Metastases; Mutation; Myeloid cells; Myelosuppression; p53 Protein; Patients; Proteins; Review boards; Side effects; Statistical analysis; Suppressor cells; Testing; Tumor proteins; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15051563

Myelosuppression is a major adverse effect of 5-fluorouracil (5-FU) chemotherapy. However, recent findings indicate that 5-FU selectively suppresses myeloid-derived suppressor cells (MDSCs), to enhance antitumor immunity in tumor-bearing mice. 5-FU-mediated myelosuppression may thus have a beneficial effect for cancer patients. The molecular mechanism underlying 5-FU's suppression of MDSCs is currently unknown. We aimed at testing the hypothesis that 5-FU suppresses MDSCs through enhancing MDSC sensitivity to Fas-mediated apoptosis. We observed that, although FasL is highly expressed in T cells, Fas is weakly expressed in myeloid cells in human colon carcinoma, indicating that downregulation of Fas is a mechanism underlying myeloid cell survival and accumulation in human colon cancer. 5-FU treatment upregulated expression of both p53 and Fas, and knocking down p53 diminished 5-FU-induced Fas expression in MDSC-like cells, in vitro. 5-FU treatment also increased MDSC-like cell sensitivity to FasL-induced apoptosis in vitro. Furthermore, we determined that 5-FU therapy increased expression of Fas on MDSCs, suppressed MDSC accumulation, and increased CTL tumor infiltration in colon tumor-bearing mice. In human colorectal cancer patients, 5-FU chemotherapy decreased MDSC accumulation and increased CTL level. Our findings determine that 5-FU chemotherapy activates the p53-Fas pathway, to suppress MDSC accumulation, to increase CTL tumor infiltration.