Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-7660, USA.
Int Immunopharmacol. 2010 Jan;10(1):140-5. doi: 10.1016/j.intimp.2009.09.023. Epub 2009 Oct 12.
Mouse mammary tumor virus-Neu (MMTV/neu) transgenic mice on an FVB-background (FVB-neuN) have increased numbers of myeloid derived suppressor cells (MDSCs) and regulatory T-cells (T-regs) in the spleen during mammary tumor induction and progression. Using this transgenic tumor model, we assessed the therapeutic activity of sunitinib, a multi-targeted, tyrosine kinase (TK) inhibitor and its effects on immune-regulatory cells. Our preliminary results show that sunitinib at 40mg/kg/day, p.o. (per os), delayed the time to tumor induction and reduced the incidence and growth of tumors in FVB-neuN mice. In association with its therapeutic activity, sunitinib reduced the absolute number of splenic T-reg cells (CD4(+)CD25(+)CD62L(+)) and MDSCs (CD11b(+)Gr1(+)) that were increased during tumor progression with less activity in mice with gross tumors. A significant decrease in the absolute number of splenic T-regs, dendritic cells (DCs), MDSCs and hematopoietic progenitors (Lin(-)Sca1(+)CD90(dull)) was observed following sunitinib treatment. The frequency of splenic T-regs and hematopoietic progenitors, but not MDSCs was also reduced by sunitinib treatment. Additionally immune-regulatory cytokines and enzymes were down regulated by sunitinib treatment, including TGFbeta and NOS2 in the spleen cells of sunitinib treated mice as compared to untreated tumor bearing (TB) mice. We conclude that sunitinib has therapeutic activity, in association with the down regulation of MDSCs and T-regs and has a trend towards the normalization of the inflammatory cytokine levels induced by tumor progression and growth. Based on these results, we suggest that sunitinib reduction of immune suppressive cells is a critical part of its adjuvant immune therapeutic activity.
FVB 背景下的鼠乳腺肿瘤病毒-Neu（MMTV/neu）转基因小鼠（FVB-neuN）在乳腺肿瘤诱导和进展过程中脾脏中髓系来源的抑制细胞（MDSCs）和调节性 T 细胞（T-regs）的数量增加。使用这种转基因肿瘤模型，我们评估了舒尼替尼的治疗活性，舒尼替尼是一种多靶点、酪氨酸激酶（TK）抑制剂，及其对免疫调节细胞的影响。我们的初步结果表明，舒尼替尼以 40mg/kg/天，口服（per os）给药，可延迟肿瘤诱导时间并减少 FVB-neuN 小鼠肿瘤的发生率和生长速度。与治疗活性相关，舒尼替尼降低了脾脏 T-reg 细胞（CD4(+)CD25(+)CD62L(+)）和 MDSCs（CD11b(+)Gr1(+)）的绝对数量，而在有明显肿瘤的小鼠中其活性降低。在舒尼替尼治疗后，观察到脾脏 T-regs、树突状细胞（DCs）、MDSCs 和造血祖细胞（Lin(-)Sca1(+)CD90(dull))的绝对数量显著减少。与舒尼替尼治疗相比，脾脏 T-regs 和造血祖细胞的频率也降低，而 MDSCs 的频率没有降低。此外，舒尼替尼治疗下调了免疫调节细胞因子和酶，包括脾脏细胞中的 TGFbeta 和 NOS2，与未治疗的肿瘤携带（TB）小鼠相比。我们得出结论，舒尼替尼具有治疗活性，与 MDSCs 和 T-regs 的下调有关，并具有使肿瘤进展和生长诱导的炎症细胞因子水平正常化的趋势。基于这些结果，我们认为舒尼替尼减少免疫抑制细胞是其辅助免疫治疗活性的关键部分。
