Zhang Yu, Wang Xue-Li, Liu Jing-Jing, Qian Zhen-Yuan, Pan Zheng-Yang, Song Ni-Ping, Chen Hui-Yan, Zhang Wei, Zhang Xin
Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People's Republic of China.
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, People's Republic of China.
J Inflamm Res. 2023 Mar 7;16:977-992. doi: 10.2147/JIR.S401123. eCollection 2023.
This study aimed to investigate the expression of inducible T-cell co-stimulator (ICOS) and its ligand (ICOSLG), along with their association with clinicopathological features and influence on the immune profile in colorectal cancer (CRC).
The Cancer Genome Atlas Colorectal Adenocarcinoma cohorts were used. We also analyzed 131 clinical samples of colon lesions, including precancerous lesions (hyperplastic polyps, low-grade dysplasia, and high-grade dysplasia) and CRC tissues. We conducted immunohistochemical (IHC) assays and multiple IHC (mIHC) of CD4+, Foxp3+ tumor-infiltrating lymphocytes (TILs), and PD-1/PD-L1 immune checkpoints in precancerous lesions and CRC samples from our patient subsets to determine changes and correlations in ICOS and ICOSLG expression during progression through the adenoma-carcinoma pathway.
High expression of ICOS and ICOSLG was a significant factor in CRC in multiple analyses and was positively correlated with CD4+/Foxp3+ TIL density and PD-1/PD-L1 expression, which increased with the sequential progression of lesions from precancerous tissues to carcinoma. Multivariable logistic regression analysis suggested that the location and expression level of ICOS/ICOSLG may be involved in precancerous-carcinoma progression. The co-expression status of PD-1 and ICOS/ ICOSLG could stratify patients with colorectal lesions into three groups of low, moderate, and high risk of progression. According to this classification and mIHC assays, we found a strong correlation between increased PD-1+ICOS+ or PD-1+ICOSLG+ co-expression and CRC, which might be deemed an independent factor in carcinogenesis.
Increased ICOS/ICOSLG expression may be associated with the progressive formation of Foxp3+ TILs in the immune microenvironment and may further promote the development of the abnormal cytology of colorectal lesions from precancerous neoplasia to CRC. Our findings support the interpretation that enhanced co-expression of PD-1+ICOS+ or PD-1+ICOSLG+ contributes to the immune-active microenvironment of the colorectal adenoma-carcinoma sequence.
本研究旨在调查诱导性T细胞共刺激分子（ICOS）及其配体（ICOSLG）的表达情况，以及它们与结直肠癌（CRC）临床病理特征的关联及其对免疫谱的影响。
使用了癌症基因组图谱结直肠腺癌队列。我们还分析了131份结肠病变的临床样本，包括癌前病变（增生性息肉、低级别异型增生和高级别异型增生）以及CRC组织。我们对患者亚组的癌前病变和CRC样本进行了免疫组织化学（IHC）检测以及CD4 +、Foxp3 +肿瘤浸润淋巴细胞（TILs）和PD-1/PD-L1免疫检查点的多重免疫组织化学（mIHC）检测，以确定在腺瘤-癌途径进展过程中ICOS和ICOSLG表达的变化及相关性。
在多项分析中，ICOS和ICOSLG的高表达是CRC的一个重要因素，并且与CD4 +/Foxp3 + TIL密度和PD-1/PD-L1表达呈正相关，随着病变从癌前组织到癌的顺序进展而增加。多变量逻辑回归分析表明，ICOS/ICOSLG的位置和表达水平可能参与癌前-癌的进展。PD-1与ICOS/ICOSLG的共表达状态可将结直肠病变患者分为低、中、高进展风险三组。根据这种分类和mIHC检测，我们发现PD-1 + ICOS +或PD-1 + ICOSLG +共表达增加与CRC之间存在强相关性，这可能被视为致癌的一个独立因素。
ICOS/ICOSLG表达增加可能与免疫微环境中Foxp3 + TILs的逐渐形成有关，并可能进一步促进结直肠病变从癌前肿瘤到CRC的异常细胞学发展。我们的研究结果支持这样的解释，即PD-1 + ICOS +或PD-1 + ICOSLG +的增强共表达有助于结直肠腺瘤-癌序列的免疫活性微环境。
