Background/Aim: The clinical response rate of prostate cancer to tyrosine kinase inhibitor (TKI) monotherapy is low

Background/Aim: The clinical response rate of prostate cancer to tyrosine kinase inhibitor (TKI) monotherapy is low. delay was only 1 1.5 days. The failure of reducing MDSCs could be the reason for resistance to Sutent treatment. MDSCs, known for their inherent immunosuppressive role, could be a prognostic factor in TKI treatment (39). We suggested that three presumable effects associated with MDSCs might diminish the efficiency of Sutent treatment: (I) The enhancement of endothelial-associated adhesion molecules, such as ICAM-1 and VCAM-1, that promotes leukocyte transmigration from the blood into tumor tissue. (II) The higher levels of pro-inflammatory factors and chemoattractants in the Sutent-treated tumor microenvironment, which facilitates the recruitment and growth of MDSCs in tumors and in the blood, respectively. (III) SRC The increased levels of chemokines, such as GM-CSF and IL-17a within SU-treated tumors, and polarization of MDSCs to support tumor progression. GM-CSF has been recognized as a potential target, especially for the growth and polarization of MDSCs (29,39). A previous study has revealed that IL-17 signaling is usually a critical mediator of the accumulation and education of MDSCs in anti-VEGF therapy (40). Consequently, our data from the multiplex immunoassay is usually consistent with those previous findings, which indicated that these specific biomarkers could be an index for evaluating tumor response to TKI therapy. Furthermore to increased quantities, we discovered that Compact disc11b+ myeloid cells re-distribute around hypoxic regions induced by lower MVD within SU-treated tumors chronically. The Compact disc68+ TAMs aggregated at chronically hypoxic areas as well as the Ly6G+ PMN-MDSCs gathered at central necrotic areas in the chronically hypoxic regions, which indicates the dissemination of specific signals from lifeless (or hypoxic) tumor cells within SU-treated tumors. In our previous studies, comparable re-distribution of CD68+ TAMs (41) and Ly6G+ PMN-MDSCs (manuscript submitted) around chronically hypoxic sites was also induced by a large single dose of radiation in the TRAMP-C1 model. Some studies have revealed that hypoxia could drive macrophages toward the M2 type, which plays a vital role in tumor growth (42). MDSCs are known to have an inherent immunosuppressive function. The accumulated MDSCs in necrotic regions within SU-treated tumors might disturb the immunity of T cells, which need tumor cell Yunaconitine debris to stimulate the subsequent immune response. However, the unique re-distribution of CD11b+ myeloid cells within the tumor is still unclear, and further investigations on myeloid cells and the physiological status of the local niche are needed. We decided the chronological response of tumor Yunaconitine microenvironment following Sutent treatment. The anti-vascular effect of TKI changed distinctly the tumor microenvironment; the vasculature was normalized, the myeloid cell lineage was re-distributed, the reduction of MDSCs both in tumor and blood was inefficient and the levels of cytokines and chemokines were increased. These effects might result in therapeutic resistance to TKI in prostate tumors. Conflicts of Interest The Authors have no conflicts of interest to declare regarding this study. Authors Contributions Sheng-Yung Fu: manuscript C writing the first draft, experimental design, analysis and interpretation of the data, methodology; Chun-Chieh Wang: manuscript C business, experimental design, concept of study, funding; Fang-Hsin Chen: manuscript – revision and editing, experimental design, methodology, concept of study, funding; Ching-Fang Yu: manuscript C revision and editing, experimental design, methodology; Ji-Hong Hong: manuscript C revision and editing, concept of study, advisor, funding; Chi-Shiun Chiang: manuscript C Yunaconitine revision, editing and approval, concept of study, advisor, funding. Acknowledgements The Yunaconitine Authors acknowledge the Radiation Biology Core Laboratory and Particle Physics and Irradiation Core Laboratory (Institute for Radiological Research, Chang Gung Memorial Hospital, Chang Gung University or college, Taoyuan, Taiwan) for scanning whole tumor sections. This study was supported by Chang Gung Memorial Hospital (CMRPG3H1691 and CMRPG3H1242) to Hong, J.H., Ministry of Technology and Technology (MOST106-2627-M-007), National Health Analysis Institutes (NHRI-EX103-10132BI), and Frontier Analysis Center inside the construction of the bigger Education Sprout Task with the Ministry of Education (MOE 107QR001I5), Taiwan to Chiang, C.S, and Chang Gung Memorial Medical center (CMRPG3H1021 and CMRPG3H1022) to Wang, C.C. Chang Gung Memorial Medical center (CIRPD1D0063) and Ministry of Research and Technology (Many107-2314-B-182-068-My2) to Chen F.H..