The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies.
The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies.
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DOI：
10.1158/0008-5472.can-08-4709
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Chen SH
中科院分区：
文献类型：
--
作者：
Ozao-Choy J;Ma G;Kao J;Wang GX;Meseck M;Sung M;Schwartz M;Divino CM;Pan PY;Chen SH
在荷瘤宿主中，髓源性抑制细胞（MDSC）和调节性T细胞（Treg）在免疫抑制中起重要作用，其逆转对于免疫治疗的成功至关重要。我们已经表明，ckit配体是MDSC积累和Treg发育所必需的。我们假设苹果酸舒尼替尼（一种受体酪氨酸激酶抑制剂）可以逆转MDSC介导的免疫抑制并调节肿瘤微环境，从而提高免疫治疗的疗效。舒尼替尼治疗降低了晚期荷瘤动物中MDSC和Treg的数量。此外，它不仅降低了MDSC的抑制功能，而且还阻止了肿瘤特异性T细胞无能和Treg发育。有趣的是，舒尼替尼治疗导致白细胞介素（IL）-10，转化生长因子-β和Foxp 3的表达减少，但Th 1细胞因子IFN-γ的表达增加，并增加了分离的肿瘤浸润性白细胞中的CTL应答。与对照组小鼠相比，舒尼替尼治疗组小鼠肿瘤中检测到显著更高的CD 8和CD 4细胞百分比和浸润。更重要的是，舒尼替尼治疗还显著降低了CD 4和CD 8 T细胞中阴性共刺激分子CTLA 4和PD-1的表达，以及MDSC和浆细胞样树突状细胞上PDL-1的表达。最后，舒尼替尼与我们的免疫治疗方案（IL-12和4-1BB激活）相结合，显着提高了大荷瘤小鼠的长期生存率。这些数据表明，舒尼替尼可用于逆转免疫抑制，并作为一个潜在的有用的辅助增强免疫为基础的癌症治疗晚期恶性肿瘤的疗效。
In tumor-bearing hosts, myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) play important roles in immune suppression, the reversal of which is vitally important for the success of immune therapy. We have shown that ckit ligand is required for MDSC accumulation and Treg development. We hypothesized that sunitinib malate, a receptor tyrosine kinase inhibitor, could reverse MDSC-mediated immune suppression and modulate the tumor microenvironment, thereby improving the efficacy of immune-based therapies. Treatment with sunitinib decreased the number of MDSC and Treg in advanced tumor-bearing animals. Furthermore, it not only reduced the suppressive function of MDSCs but also prevented tumor-specific T-cell anergy and Treg development. Interestingly, sunitinib treatment resulted in reduced expression of interleukin (IL)-10, transforming growth factor-β, and Foxp3 but enhanced expression of Th1 cytokine IFN-γ and increased CTL responses in isolated tumor-infiltrating leukocytes. A significantly higher percentage and infiltration of CD8 and CD4 cells was detected in tumors of sunitinib-treated mice when compared with control-treated mice. More importantly, the expression of negative costimulatory molecules CTLA4 and PD-1 in both CD4 and CD8 T cells, and PDL-1 expression on MDSC and plasmacytoid dendritic cells, was also significantly decreased by sunitinib treatment. Finally, sunitinib in combination with our immune therapy protocol (IL-12 and 4-1BB activation) significantly improves the long-term survival rate of large tumor-bearing mice. These data suggest that sunitinib can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune-based cancer therapy for advanced malignancies.