Curio Sophie, Lin Wanzun, Bromley Christian, McGovern Jenny, Triulzi Chiara, Jonsson Gustav, Ghislat Ghita, Zelenay Santiago, Guerra Nadia
Department of Life Sciences, Imperial College London, London SW7 2BX, UK.
The University of Queensland Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD 4102, Australia.
Cancers (Basel). 2023 Mar 16;15(6):1792. doi: 10.3390/cancers15061792.
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 ) and NKG2D ligand gene expression is elevated in the most immunogenic subset of CRC patients. High level of positively correlated with the mRNA expression of and associated with a poor survival of CRC patients. We further show that NKG2D deficiency in the 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.
由于免疫、临床和病理情况的异质性，治疗结直肠癌（CRC）是一项重大挑战。到目前为止，免疫疗法仅在非常有限的一部分CRC患者中被证明有效。为了更好地定义免疫情况，我们检查了CRC患者各个亚组中的免疫基因表达谱，并使用肠道肿瘤小鼠模型来剖析免疫功能。我们发现，NK细胞受体自然杀伤细胞2族成员D（NKG2D，由[此处缺失相关基因名称]编码）及其配体基因表达在CRC患者最具免疫原性的亚组中升高。[此处缺失相关物质]的高水平与[此处缺失相关基因名称]的mRNA表达呈正相关，并与CRC患者的不良生存相关。我们进一步表明，在肠道肿瘤发生的小鼠模型中NKG2D缺陷导致肿瘤内IFNγ产生减少、肿瘤发生减少以及生存期延长，这表明在CRC患者肿瘤中观察到的高水平IFNγ可能是NKG2D激活的结果。本研究中突出显示的NKG2D对CRC进展作用的机制将引发关于以下方面的讨论：（i）在CRC患者中靶向NKG2D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必要性。
