Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland.
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Ann Surg Oncol. 2021 Nov;28(12):7999-8006. doi: 10.1245/s10434-021-09873-4. Epub 2021 Apr 19.
Immune checkpoint inhibition has demonstrated success in overcoming tumor-mediated immune suppression in several types of cancer. However, its clinical use is limited to a small subset of colorectal cancer (CRC) patients, and response is highly variable between CRC subtypes. This study aimed to determine the profile of immune checkpoints and factors associated with immune checkpoint inhibitor response in mucinous CRC.
Gene expression data from CRC was extracted from the TCGA PanCanAtlas data-freeze release. Gene expression data were reported as batch-corrected and normalized RNA expression derived from RNA-Seq quantification. Clinical, pathologic, and transcriptomic data were compared between mucinous and non-mucinous CRC cohorts.
The 557 cases of CRC eligible for inclusion in this study comprised 486 cases of non-mucinous CRC (87.3 %) and 71 cases of mucinous CRC (12.7 %). High correlation was observed in the expression of the included immune checkpoints. Significantly higher expression of programmed cell death protein 1 ligand (PD-L1) and T cell immunoglobulin and mucin domain 3 (TIM-3) was observed in mucinous CRC than in non-mucinous CRC. In a multiple regression model, significant contributors to the prediction of TIM-3 gene expression were microsatellite instability (MSI) (unstandardized regression coefficient [B] = 1.223; p < 0.001), stage (American Joint Committee on Cancer [AJCC] 2; B = 0.423; p < 0.05), and mucinous status (B = 0.591; p < 0.01).
Expression of TIM-3, an emerging immune checkpoint inhibition target, was significantly higher in mucinous CRC, and expression was predicted by mucinous status independently of MSI. These findings should prompt investigation of immune checkpoint signaling in the mucinous tumor microenvironment to clarify the potential for immune checkpoint inhibition in mucinous CRC.
免疫检查点抑制已在多种类型的癌症中证明成功克服了肿瘤介导的免疫抑制。然而，其临床应用仅限于一小部分结直肠癌（CRC）患者，并且 CRC 亚型之间的反应差异很大。本研究旨在确定黏蛋白 CRC 中免疫检查点的特征和与免疫检查点抑制剂反应相关的因素。
从 TCGA PanCanAtlas 数据冻结释放中提取 CRC 的基因表达数据。基因表达数据报告为批次校正和标准化的 RNA 表达，源自 RNA-Seq 定量。比较黏蛋白和非黏蛋白 CRC 队列之间的临床、病理和转录组数据。
本研究纳入的 557 例 CRC 病例中，486 例为非黏蛋白 CRC（87.3%），71 例为黏蛋白 CRC（12.7%）。所包括的免疫检查点的表达高度相关。黏蛋白 CRC 中程序性细胞死亡蛋白 1 配体（PD-L1）和 T 细胞免疫球蛋白和粘蛋白结构域 3（TIM-3）的表达明显高于非黏蛋白 CRC。在多元回归模型中，对 TIM-3 基因表达有显著预测作用的因素包括微卫星不稳定性（MSI）（未标准化回归系数 [B] = 1.223；p < 0.001）、分期（美国癌症联合委员会 [AJCC] 2 期；B = 0.423；p < 0.05）和黏蛋白状态（B = 0.591；p < 0.01）。
黏蛋白 CRC 中 TIM-3 的表达明显更高，这是一种新兴的免疫检查点抑制靶点，其表达独立于 MSI 由黏蛋白状态预测。这些发现应促使在黏蛋白肿瘤微环境中研究免疫检查点信号，以阐明黏蛋白 CRC 中免疫检查点抑制的潜力。
