CD38-Expressing Myeloid-Derived Suppressor Cells Promote Tumor Growth in a Murine Model of Esophageal Cancer.
CD38-Expressing Myeloid-Derived Suppressor Cells Promote Tumor Growth in a Murine Model of Esophageal Cancer.
复制标题
DOI：
10.1158/0008-5472.can-14-3639
复制
发表时间：
2015-10-01
期刊：
影响因子：
11.2
通讯作者：
Rustgi AK
中科院分区：
文献类型：
--
作者：
Karakasheva TA;Waldron TJ;Eruslanov E;Kim SB;Lee JS;O'Brien S;Hicks PD;Basu D;Singhal S;Malavasi F;Rustgi AK
髓源性抑制细胞(MDSCs)是一种免疫抑制的未成熟髓系细胞群体，发现于晚期癌症患者和小鼠肿瘤模型中。诱导型一氧化氮合酶(INOS)和精氨酸酶的产生以及其他抑制机制使MDSCs能够抑制T细胞介导的肿瘤清除，促进肿瘤进展。利用一种无偏见的全局基因表达方法，在口腔食道癌的模型-条件性p120-catenin基因敲除小鼠(L2-cre；p120ctnf/f)中，我们确定CD38在MDSC生物学中发挥重要作用，这是以前未知的。CD38属于ADP核糖环化酶家族，兼具胞外酶和受体功能。据报道，它在淋巴和早期髓系细胞分化、细胞激活和中性粒细胞趋化中发挥作用。我们发现，在其他食道癌的小鼠肿瘤模型中，CD38在MDSC中的表达也很明显，并且CD38高表达的MDSCs比缺乏CD38表达的MDSCs更不成熟，这表明CD38在MDSC群体中发现的成熟停滞中可能起到了作用。与CD38low MDSCs相比，CD38High MDSCs也具有更强的抑制活化T细胞的能力，并在更大程度上促进肿瘤生长，这可能是iNOS产生增加的结果。此外，我们还鉴定了新的肿瘤衍生因子，特别是IL-6、IGFBP-3和CXCL16，它们可以在体外诱导MDSCs表达CD38。最后，我们检测到晚期癌症患者外周血中CD38阳性MDSCs的扩张，并验证了体内靶向CD38是一种新的癌症治疗方法。
Myeloid derived suppressor cells (MDSCs) are an immunosuppressive population of immature myeloid cells found in advanced stage cancer patients and mouse tumor models. Production of inducible nitric oxide synthase (iNOS) and arginase, as well as other suppressive mechanisms, allow MDSCs to suppress T cell-mediated tumor clearance and foster tumor progression. Using an unbiased global gene expression approach in conditional p120-catenin knockout mice (L2-cre;p120ctnf/f), a model of oral-esophageal cancer, we have identified CD38 as playing a vital role in MDSC biology, previously unknown. CD38 belongs to the ADP-ribosyl cyclase family and possesses both ectoenzyme and receptor functions. It has been described to function in lymphoid and early myeloid cell differentiation, cell activation and neutrophil chemotaxis. We find that CD38 expression in MDSCs is evident in other mouse tumor models of esophageal carcinogenesis, and CD38high MDSCs are more immature than MDSCs lacking CD38 expression, suggesting a potential role for CD38 in the maturation halt found in MDSC populations. CD38high MDSCs also possess a greater capacity to suppress activated T cells, and promote tumor growth to a greater degree than CD38low MDSCs, likely as a result of increased iNOS production. Additionally, we have identified novel tumor-derived factors, specifically IL-6, IGFBP-3 and CXCL16, which induce CD38 expression by MDSCs ex vivo. Finally, we have detected an expansion of CD38-positive MDSCs in peripheral blood of advanced stage cancer patients and validated targeting CD38 in vivo as a novel approach to cancer therapy.