NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer.
NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer.
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NKG2D是一种免疫受体，表达在几个淋巴细胞亚群上，参与识别和消除感染细胞和癌细胞。NKG2D作为癌症治疗靶点的发现导致了新的免疫治疗策略的开发，旨在激活免疫系统来对抗各种类型的癌症。我们的研究探讨了NKG2D在结直肠癌中的作用。我们发现，与在其他癌症类型中观察到的保护作用相反，NKG2D的高表达与部分患者的生存率下降有关。我们的工作强调，在晚期肿瘤中，表达NKG2D的细胞的存在并不总是一个良好的预后标志，需要更多的研究来充分了解其作用机制，并调查基于NKG2D的治疗在结直肠癌中的有效性和安全性。由于免疫、临床和病理的异质性，结直肠癌(CRC)的治疗是一个重大挑战。到目前为止，免疫疗法仅在非常有限的结直肠癌患者亚群中被证明有效。为了更好地定义免疫格局，我们检查了结直肠癌患者不同亚群的免疫基因表达谱，并使用肠道肿瘤的小鼠模型来剖析免疫功能。我们发现NK细胞受体、自然杀伤分子2成员D(NKG2D，由KLRK1编码)和NKG2D配体基因在大多数免疫原性结直肠癌患者中表达升高。KLRK1的高水平与IFNG的mRNA表达呈正相关，并与患者的生存不良有关。我们进一步表明，在Apcmin/+小鼠的肠道肿瘤形成模型中，NKG2D缺乏导致肿瘤内干扰素γ的产生减少，肿瘤形成减少，并提高了存活率，这表明在结直肠癌患者的肿瘤中观察到高水平的干扰素γ可能是NKG2D参与的结果。这项研究中强调的NKG2D对CRC进展的作用机制将推动关于(I)靶向NKG2D在结直肠癌患者中的益处以及(Ii)确定NKG2D和NKG2D配体表达在不同肿瘤类型中的预测价值的讨论。
NKG2D is a type of immune receptor that is expressed on several subsets of lymphocytes and involved in the recognition and elimination of infected cells and cancer cells. The discovery of NKG2D as a therapeutic target for cancer has led to the development of novel immunotherapy strategies that aim to activate the immune system to fight various types of cancer. Our study explores the role played by NKG2D in colorectal cancer. We show that high expression of NKG2D is associated with decreased survival in a subset of patients, in contrast with the protective role observed in other cancer types. Our work highlights that the presence of NKG2D-expressing cells is not always a good prognostic marker in advanced tumors, and that more research is needed to fully understand its mechanisms of action and investigate the efficacy and safety of NKG2D-based therapy in colorectal cancer. Treating colorectal cancer (CRC) is a major challenge due to the heterogeneous immunological, clinical and pathological landscapes. Immunotherapy has so far only proven effective in a very limited subgroup of CRC patients. To better define the immune landscape, we examined the immune gene expression profile in various subsets of CRC patients and used a mouse model of intestinal tumors to dissect immune functions. We found that the NK cell receptor, natural-killer group 2 member D (NKG2D, encoded by KLRK1) and NKG2D ligand gene expression is elevated in the most immunogenic subset of CRC patients. High level of KLRK1 positively correlated with the mRNA expression of IFNG and associated with a poor survival of CRC patients. We further show that NKG2D deficiency in the Apcmin/+ mouse model of intestinal tumorigenesis led to reduced intratumoral IFNγ production, reduced tumorigenesis and enhanced survival, suggesting that the high levels of IFNγ observed in the tumors of CRC patients may be a consequence of NKG2D engagement. The mechanisms governing the contribution of NKG2D to CRC progression highlighted in this study will fuel discussions about (i) the benefit of targeting NKG2D in CRC patients and (ii) the need to define the predictive value of NKG2D and NKG2D ligand expression across tumor types.
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DOI：
10.1158/1078-0432.ccr-09-0991
发表时间：
2009-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
McGilvray RW;Eagle RA;Watson NF;Al-Attar A;Ball G;Jafferji I;Trowsdale J;Durrant LG
通讯作者：
Durrant LG
影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
29.4
作者：
Allez, Matthieu;Tieng, Vannary;Toubert, Antoine
通讯作者：
Toubert, Antoine
影响因子：
11.5
作者：
Fernandez, Lucia;Metais, Jean-Yves;Perez-Martinez, Antonio
通讯作者：
Perez-Martinez, Antonio
影响因子：
5.1
作者：
通讯作者：
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