Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape.
Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape.
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DOI：
10.3109/08820139.2012.703745
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发表时间：
2012
影响因子：
2.8
通讯作者：
Finke JH
中科院分区：
文献类型：
--
作者：
Cohen PA;Ko JS;Storkus WJ;Spencer CD;Bradley JM;Gorman JE;McCurry DB;Zorro-Manrique S;Dominguez AL;Pathangey LB;Rayman PA;Rini BI;Gendler SJ;Finke JH
受体酪氨酸激酶抑制剂舒尼替尼能够非常有效地减少血液（人类）和脾脏（小鼠）等外周组织中的 MDSC，恢复旁观者 T 淋巴细胞对 TcR 刺激的反应性。舒尼替尼可阻断未分化 MDSC 的增殖，并降低分化程度较高的中性粒细胞 MDSC (n-MDSC) 后代的存活率。具有讽刺意味的是，即使完全没有可检测到的抗肿瘤治疗反应，舒尼替尼的深远影响也被观察到。最好的解释是，各个身体部位内存在不同的 MDSC 调节刺激，从而允许对舒尼替尼的敏感性和耐药性在同一只小鼠或患者体内共存。 GM-CSF 的存在或缺失可能是每个区室中的主要决定因素，因为 GM-CSF 具有抢占 STAT3 依赖性和显性 STAT5 依赖性造血编程的能力，赋予舒尼替尼耐药性，并将分化从 n-MDSC 谱系重定向到更通用的单核细胞 (m-MDSC) 谱系。舒尼替尼的临床经验强调，MDSC 和 Treg 消耗策略必须注意身体区室之间的差异，以避免避难所效应。具有讽刺意味的是，表现出对舒尼替尼耐药的 m-MDSC 也具有分化为杀肿瘤辅助细胞的最大潜力，因为它们能够响应 T 细胞分泌的 IFN-γ 或产生一氧化氮和过氧硝酸盐的 TLR 激动剂。
The receptor tyrosine kinase inhibitor, sunitinib, is astonishingly effective in its capacity to reduce MDSCs in peripheral tissues such as blood (human) and spleen (mouse), restoring responsiveness of bystander T lymphocytes to TcR stimulation. Sunitinib blocks proliferation of undifferentiated MDSCs and decreases survival of more differentiated neutrophilic MDSC (n-MDSC) progeny. Ironically, sunitinib’s profound effects are observed even in a total absence of detectable anti-tumor therapeutic response. This is best explained by the presence of disparate MDSC-conditioning stimuli within individual body compartments, allowing sensitivity and resistance to sunitinib to coexist within the same mouse or patient. The presence or absence of GM-CSF is likely the major determinant in each compartment, given that GM-CSF’s capacity to preempt STAT3-dependent with dominant STAT5-dependent hematopoietic programming confers sunitinib resistance and redirects differentiation from the n-MDSC lineage to the more versatile monocytoid (m-MDSC) lineage. The clinical sunitinib experience underscores that strategies for MDSC and Treg depletions must be mindful of disparities among body compartments to avoid sanctuary effects. Ironically, m-MDSCs manifesting resistance to sunitinib also have the greatest potential to differentiate into tumoricidal accessory cells, by virtue of their capacity to respond to T cell-secreted IFN-γ or to TLR agonists with nitric oxide and peroxynitrate production.
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影响因子：
4.4
作者：
Almand, B;Clark, JI;Gabrilovich, DI
通讯作者：
Gabrilovich, DI
影响因子：
64.8
作者：
GERSHON, RK;EARDLEY, DD;PTAK, W
通讯作者：
PTAK, W
影响因子：
4.4
作者：
Bronte, V;Serafini, P;Zanovello, P
通讯作者：
Zanovello, P
影响因子：
254.7
作者：
Garcia, Jorge A.;Rini, Brian I.
通讯作者：
Rini, Brian I.
DOI：
10.1073/pnas.80.12.3779
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
HU, SK;EARDLEY, DD;GERSHON, RK
通讯作者：
GERSHON, RK