MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy.
MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy.
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DOI：
10.1016/j.intimp.2011.01.030
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发表时间：
2011-07
影响因子：
5.6
通讯作者：
Cohen, Peter
中科院分区：
文献类型：
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作者：
Finke, James;Ko, Jennifer;Rini, Brian;Rayman, Pat;Ireland, Joanna;Cohen, Peter
舒尼替尼是一种受体酪氨酸激酶抑制剂(TKI)，是转移性肾细胞癌(MRCC)的一线治疗药物。其抗肿瘤活性与其通过多种TKI受体(血管内皮生长因子受体、血小板衍生生长因子、干细胞因子)阻断肿瘤细胞和肿瘤血管细胞信号传导有关。在肾细胞癌患者和小鼠肿瘤模型中，舒尼替尼还靶向髓系抑制细胞(MDSCs)，显着减少它们在外周血中的积聚，并逆转T细胞(干扰素γ)抑制。这种免疫抑制的减少为将舒尼替尼与免疫疗法结合用于治疗某些类型的肿瘤提供了理论基础。然而，尽管有这些令人鼓舞的发现，我们观察到舒尼替尼在减少肿瘤微环境中的MDSCs和恢复T细胞功能方面有不同的影响。考虑到MDSC的免疫抑制和促血管生成活性，它们的持久性似乎可能有助于舒尼替尼治疗患者的耐药性发展。虽然舒尼替尼减少了Renca和CT26荷瘤小鼠的肿瘤浸润性MDSCs，与肿瘤大小的强烈到适度的减小相吻合，但它在减少MDSCs(Gr1+CD11b+减少35%)或4T1荷瘤小鼠的肿瘤负担方面无效。肿瘤内MDSCs的持续存在与肿瘤内T细胞干扰素γ反应的抑制和GM-CSF表达的增加平行。此外，体外和体内实验表明，GM-CSF延长了MDSCs的存活时间，从而通过依赖pSTAT5的途径保护它们免受Sunitinib的影响。虽然是初步的，但有证据表明，在接受舒尼替尼治疗的一些肾细胞癌患者中，肿瘤内存在MDSC耐药。在新辅助环境下接受舒尼替尼治疗的肾癌患者接受肾切除术后的肿瘤内多药耐受能力和T细胞干扰素γ应答情况与接受肾癌切除术但未事先接受舒尼替尼治疗的患者进行比较。未治疗患者的肿瘤显示T细胞干扰素γ反应受到抑制，同时MDSCs大量表达(占总消化细胞的5%)。到目前为止，来自5/8新辅助治疗患者的肿瘤在舒尼替尼治疗后显示肿瘤内MDSCs持续存在和低T细胞干扰素γ产生，这一结果与未经治疗的肿瘤相似。在其余3例新辅助治疗患者中，肿瘤内MDSCs检测到低水平，这与T细胞干扰素γ反应相似，与正常供者外周T细胞的反应相似。GM-CSF在促进患者肿瘤中MDSC存活方面的作用得到了以下观察的支持：GM-CSF在短期肾癌培养中产生的水平能够保护MDSC免受舒尼替尼诱导的细胞死亡。此外，MDSC的持续存在也可能与肿瘤间质细胞或浸润性MDSC产生的促血管生成蛋白如MMP9、MMP8和IL-8的表达增加有关。事实上，我们的发现表明，肾癌患者中最主要的MDSC亚群是产生促血管生成蛋白的中性粒细胞群体。我们认为，肿瘤内MDSCs的存活部分介导了舒尼替尼耐药性的发展，从而提供了持续的免疫抑制和血管生成。
Sunitinib is a receptor tyrosine kinase inhibitor (TKI) that is front-line therapy for metastatic renal cell carcinoma (mRCC). Its antitumor activity is related to its ability to block tumor cell and tumor vasculature cell signaling via several TKI receptors (i.e. vascular endothelial growth factor receptors VEGFRs, platelet-derived growth factors (PDGFs), stem cell factors). Sunitinib also targets myeloid derived suppressor cells (MDSCs) significantly reducing their accumulation in the peripheral blood and reversing T cell (IFNγ) suppression in both mRCC patients and in murine tumor models. This reduction in immune suppression provides a rationale for combining sunitinib with immunotherapy for the treatment of certain tumor types. Despite these encouraging findings, however, we have observed that sunitinib has variable impact at reducing MDSCs and restoring T cell function within the tumor microenvironment. Given the immunosuppressive and proangiogenic activities of MDSC, it seems plausible that their persistence may contribute to the resistance that develops in sunitinib-treated patients. While sunitinib reduced tumor infiltrating MDSCs in Renca and CT26-bearing mice, coinciding with strong to modest decreases in tumor size respectively, it was ineffective at ‘reducing MDSCs (<35% reduction in Gr1+CD11b+) or tumor burden in 4T1-bearing mice. Persistence of intratumor MDSCs was paralleled by depressed intratumor T cell IFNγ response and increased GM-CSF expression. Additionally, in vitro and in vivo experiments showed that GM-CSF prolongs survival of MDSCs, thus protecting them from the effects of sunitinib via a pSTAT5-dependent pathway. Although preliminary, there is evidence of intratumor MDSC resistance in some mRCC patients following sunitinib treatment. Intratumor MDSC persistence and T cell IFNγ response post nephrectomy in patients receiving sunitinib in a neoadjuvant setting is being compared to RCC patients undergoing nephrectomy without prior sunitinib treatment. Tumors from untreated patients showed suppressed T cell IFNγ response along with substantial expression of MDSCs (5% of total digested cells). Thus far, tumors from 5/8 neoadjuvant patients showed persistence of intratumor MDSCs and low T cell IFNγ production post sunitinib treatment, findings that parallel results from untreated tumors. In the remaining 3 neoadjuvant patients, intratumor MDSCs were detected at low levels which coincided with a T cell IFNγ response similar to that observed with normal donor peripheral T cells. GM-CSF’s role in promoting MDSC survival in patient tumors is supported by the observation that GM-CSF is produced in short-term RCC cultures at levels capable of protecting MDSCs from sunitinib-induced cell death. Additionally, persistence of MDSC also may be associated with increased expression of proangiogenic proteins, such as MMP9, MMP8, and IL-8 produced by tumor stromal cells or infiltrating MDSCs. Indeed our findings suggest that the most dominate MDSC subset in RCC patients is the neutrophilic population that produces proangiogenic proteins. We propose that the development of sunitinib resistance is partly mediated by the survival of MDSCs intratumorally, thereby providing sustained immune suppression and angiogenesis.
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影响因子：
11.2
作者：
Ozao-Choy J;Ma G;Kao J;Wang GX;Meseck M;Sung M;Schwartz M;Divino CM;Pan PY;Chen SH
通讯作者：
Chen SH
影响因子：
11.5
作者：
Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
影响因子：
11.2
作者：
Serafini, P;Carbley, R;Borrello, I
通讯作者：
Borrello, I
影响因子：
11.2
作者：
Rodriguez PC;Ernstoff MS;Hernandez C;Atkins M;Zabaleta J;Sierra R;Ochoa AC
通讯作者：
Ochoa AC
影响因子：
8.8
作者：
通讯作者：
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