T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice.
T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice.
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T淋巴细胞SHP2缺陷触发抗肿瘤免疫抑制小鼠结肠炎相关癌症
DOI：
10.18632/oncotarget.13812
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发表时间：
2017-01-31
期刊：
影响因子：
--
通讯作者：
Sun Y
中科院分区：
文献类型：
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作者：
Liu W;Guo W;Shen L;Chen Z;Luo Q;Luo X;Feng G;Shu Y;Gu Y;Xu Q;Sun Y
非消退性炎症参与肿瘤发生的起始和进展过程。已知含有Src同源2结构域的酪氨酸磷酸酶2（SHP 2）抑制急性炎症，但其在慢性炎症相关癌症中的作用仍不清楚。使用SHP 2CD 4 −/−条件性敲除小鼠检测了SHP 2在葡聚糖硫酸钠（DSS）诱导的结肠炎和氧化偶氮甲烷-DSS诱导的结肠炎相关致癌作用中T细胞中的作用。T细胞中的SHP 2缺陷加重结肠炎，其中促炎细胞因子包括IFN-γ和IL-17 A的水平增加。相比之下，SHP 2CD 4 −/−小鼠比野生型小鼠产生的肿瘤更少，更小，IFN-γ水平更高，肿瘤和肿瘤周围区域的CD 8 + T细胞的细胞毒性增强。在分子水平上，STAT 1在缺乏SHP 2的T细胞中过度磷酸化，这可能是Th 1分化和IFN-γ分泌增加的原因。IFN-γ中和或IFN-γ受体敲除而非IL-17 A中和，消除了SHP 2敲除的抗肿瘤作用，穿孔素1、FasL和颗粒酶B水平降低。最后，颗粒酶B的表达与人类结肠癌患者的恶性程度呈负相关。总之，这些发现提出了一种通过靶向SHP 2治疗结肠炎相关癌症的新策略。
Nonresolving inflammation is involved in the initiation and progression process of tumorigenesis. Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is known to inhibit acute inflammation but its role in chronic inflammation-associated cancer remains unclear. The role of SHP2 in T cells in dextran sulfate sodium (DSS)-induced colitis and azoxymethane-DSS-induced colitis-associated carcinogenesis was examined using SHP2CD4−/− conditional knockout mice. SHP2 deficiency in T cells aggravated colitis with increased level of pro-inflammatory cytokines including IFN-γ and IL-17A. In contrast, the SHP2CD4−/− mice developed much fewer and smaller tumors than wild type mice with higher level of IFN-γ and enhanced cytotoxicity of CD8+ T cells in the tumor and peritumoral areas. At the molecular level, STAT1 was hyper-phosphorylated in T cells lacking SHP2, which may account for the increased Th1 differentiation and IFN-γ secretion. IFN-γ neutralization or IFN-γ receptor knockout but not IL-17A neutralization, abrogated the anti-tumor effect of SHP2 knockout with lowered levels of perforin 1, FasL and granzyme B. Finally, the expression of granzyme B was negatively correlated with the malignancy of colon cancer in human patients. In conclusion, these findings suggest a new strategy to treat colitis-associated cancer via targeting SHP2.