EXTH-69. REGULATION OF N1/N2 NEUTROPHIL PHENOTYPE BY A MANZAMINE-DERIVED COMPOUND FOR BRAIN TUMOR TREATMENT

Abstract In cancer microenvironment, the presence of neutrophils is associated with tumor proliferation, invasion and immunomodulation. The tumor associated neutrophils (TAN) can be polarized toward N1 (anti-tumor) or N2 (pro-tumor) phenotypes. Therefore, modulating neutrophil phenotype may serve as brain tumor treatment strategy. We use immunosuppressive and normal mice bearing brain tumor cell xenograft to study the role of TANs in tumor progression. A manzamine-derived compound 1-(9’-propyl-3’-carbazole)-1, 2, 3, 4-tetrahydro-β-carboline (PCTC) was used to treat brain tumor mice. In brain tumor tissue, flowcytometry study revealed the amount of pro-tumor N2 TAN is significantly greater than anti-tumor N1 subtype. While PCTC was intracranial administrated into brain tumor, the ratio of N1/N2 is reversed. Immunochemical staining showed increasing neutrophils in tumor at day 1 post treatment, followed by subsequent T cell and macrophage gathering at day 5. Cytokine array results revealed the expression level of CXCL9/CXCL10 were upregulated in PCTC treatment glioma cells and brain tumor tissues. Cell study also demonstrated T cell migration ability was significantly increased when co-cultured with neutrophil and PCTC treated glioma cells. In mice tumor model, NU/NU mouse lack of T cell represented no response to PCTC treatment, while significant tumor shrunken was observed in B6 mice. Compensation study by intravenous inoculation of T cell and PCTC to NU/NU glioma mice showed flavor response to animal survival. In this study, we demonstrated the N1/N2 ratio of TAN can be regulated by PCTC, and be beneficial to glioma treatment. Furthermore, PCTC acts on tumor cells, together with TAN to attract T cell by increase CXCL9/CXCL10. Anti-tumor N1 and subsequent T cell gathering both contribute to tumor cell killing. As a conclusion, neutrophil phenotype can be modulated, and cooperated with T cells to serve as a new glioma treatment strategy.