Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
J Immunother Cancer. 2024 Nov 5;12(11):e010326. doi: 10.1136/jitc-2024-010326.
In patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-high tumors. Meanwhile, new immunotherapies targeting the innate immune system are attracting increasing attention. CD47 is a representative innate immune checkpoint involved in the evasion of tumor cell phagocytosis by macrophages. This large-scale study comprehensively examined the molecular significance of gene expression in CRC.
We analyzed the next-generation sequencing data of DNA and RNA from 14,287 CRC cases included in the data set of a commercial Clinical Laboratory Improvement Amendments-certified laboratory (Caris Life Sciences). The cases were divided into two groups based on the median value of gene expression levels. The molecular and immune profiles between the groups were compared, and the relationship between expression and survival outcomes was further examined.
In -high tumors, the proportion of consensus molecular subtypes 1 and 4 was significantly higher than in -low tumors. The expression levels of damage-associated molecular pattern-related genes showed a positive correlation with expression levels. Major oncogenic pathways, such as mitogen-activated protein kinase, phosphoinositide 3-kinase, angiogenesis, and transforming growth factor beta, were significantly activated in -high tumors. Additionally, the expression levels of a panel of adaptive immune checkpoint genes and estimates of immune cells constituting the tumor microenvironment (TME) were significantly higher in -high tumors.
expression in CRC was associated with the activation of several oncogenic pathways and an immune-engaged TME. Our findings may provide valuable information for considering new therapeutic strategies targeting innate immune checkpoints in CRC.
在结直肠癌（CRC）患者中，针对适应性免疫系统的常规免疫检查点抑制剂的治疗效果在很大程度上仅限于微卫星不稳定高肿瘤患者。与此同时，针对固有免疫系统的新免疫疗法正受到越来越多的关注。CD47 是一种参与巨噬细胞逃避肿瘤细胞吞噬的代表性固有免疫检查点。这项大规模研究全面检查了 CRC 中基因表达的分子意义。
我们分析了来自 Caris 生命科学公司的商业临床实验室改进修正案认证实验室数据集中包含的 14287 例 CRC 病例的 DNA 和 RNA 下一代测序数据。根据基因表达水平的中位数将病例分为两组。比较两组之间的分子和免疫特征，并进一步研究表达与生存结果之间的关系。
在高肿瘤中，共识分子亚型 1 和 4 的比例明显高于低肿瘤。损伤相关分子模式相关基因的表达水平与表达水平呈正相关。主要致癌途径，如丝裂原激活蛋白激酶、磷酸肌醇 3-激酶、血管生成和转化生长因子β，在高肿瘤中明显激活。此外，适应性免疫检查点基因的表达水平和构成肿瘤微环境（TME）的免疫细胞的估计在高肿瘤中明显更高。
CRC 中的表达与几种致癌途径的激活和免疫参与的 TME 相关。我们的发现可能为考虑针对 CRC 固有免疫检查点的新治疗策略提供有价值的信息。
