Multiplex immunohistochemistry defines the tumor immune microenvironment and immunotherapeutic outcome in CLDN18.2-positive gastric cancer.
Multiplex immunohistochemistry defines the tumor immune microenvironment and immunotherapeutic outcome in CLDN18.2-positive gastric cancer.
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多重免疫组织化学技术可明确CLDN18.2阳性胃癌的肿瘤免疫微环境及免疫治疗效果。
DOI：
10.1186/s12916-022-02421-1
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发表时间：
2022-07-11
期刊：
影响因子：
9.3
通讯作者：
Shen, Lin
中科院分区：
文献类型：
--
作者：
Jia, Keren;Chen, Yang;Sun, Yu;Hu, Yajie;Jiao, Lei;Ma, Jie;Yuan, Jiajia;Qi, Changsong;Li, Yanyan;Gong, Jifang;Gao, Jing;Zhang, Xiaotian;Li, Jian;Zhang, Cheng;Shen, Lin
FAST研究将claudin-18（CLDN18.2）确定为胃癌（GC）的有希望的新治疗靶点。然而，CLDN18.2阳性胃癌的肿瘤免疫微环境和临床病理特征尚不清楚，这使得难以开发和优化CLDN18.2靶向治疗。本研究纳入了80例GC患者，其中60例接受了抗PD-1/PD-L1治疗。使用多重免疫组织化学（m-IHC）标记CD 4/CD 8/CD 20/CD 66 B/CD 68/CD 163/PD-1/PD-L1/TIM-3/LAG-3/FoxP 3/CTLA-4/HLA-DR/STING和CLDN18.2，以解读从这些患者分离的福尔马林固定、石蜡包埋的肿瘤组织中T细胞、B细胞、巨噬细胞和嗜中性粒细胞的比率和空间分布。分别使用两个独立样本t检验和对数秩检验分析肿瘤免疫微环境特征和通过CLDN18.2表达分层的患者存活率。我们认为中等至强CLDN18.2表达≥ 40%的肿瘤细胞作为阳性的截止值。CLDN18.2阳性肿瘤中CD 8 +PD-1−、CD 8 +LAG-3−和CD 8 +TIM-3− T细胞的比例显著高于阴性肿瘤（分别为0.039 vs. 0.026，P = 0.009; 0.050 vs.0.035，P = 0.024; 0.045 vs. 0.032，P = 0.038）。此外，中性粒细胞（CD 66 b+）的数量在CLDN18.2阳性组中高于阴性组（分别为0.081 vs. 0.055，P = 0.031），而M1 CLDN18.2阳性组和阴性组之间的CD 68 + CD 163 − HLA-DR+、M2巨噬细胞（CD 68 + CD 163 +HLA-DR−）和B细胞（CD 20+）相当。CLDN18.2阳性肿瘤中肿瘤细胞周围20 μm范围内的CD 8 +PD-1−、CD 8 +LAG-3−和CD 8 +TIM-3−T细胞的平均数量高于CLDN18.2阴性肿瘤（分别为0.16 vs. 0.09，P = 0.011; 0.20 vs. 0.12，P = 0.029; 0.18 vs. 0.12，P = 0.047）。此外，在CLDN18.2阳性组中，在20 μm范围内被CD 8 +PD-1−、CD 8 +LAG-3− T细胞或M1巨噬细胞包围的肿瘤细胞占所有肿瘤细胞的比例高于CLDN18.2阴性组（分别为10.79% vs. 6.60%，P = 0.015; 12.68% vs. 8.70%，P = 0.049; 9.08% vs. 6.56%，P = 0.033）。这些发现表明CLDN18.2阳性GC具有复杂的免疫微环境特征。此外，CLDN18.2阳性组的OS和irOS均短于CLDN18.2阴性组（中位OS：23.33 vs.36.6个月，P < 0.001;中位irOS：10.03 vs.20.13个月，P = 0.044）。CLDN 18. 2阳性胃癌具有独特的免疫微环境特征，这对CLDN 18. 2靶向治疗的研究具有重要意义。然而，CLDN18.2相关微环境特征对预后的影响需要进一步研究。在线版本包含补充材料，可通过10.1186/s12916-022-02421-1获得。
The FAST study identified claudin-18 (CLDN18.2) as a promising novel therapeutic target for gastric cancer (GC). However, the tumor immune microenvironment and clinicopathological features of CLDN18.2-positive GC are unclear, making it difficult to develop and optimize CLDN18.2-targeted treatments. This study included 80 GC patients, 60 of whom received anti-PD-1/PD-L1 treatment. CD4/CD8/CD20/CD66b/CD68/CD163/PD-1/PD-L1/TIM-3/LAG-3/FoxP3/CTLA-4/HLA-DR/STING, and CLDN18.2 were labeled using multiplex immunohistochemistry (m-IHC) to decipher the rate and spatial distribution of T cells, B cells, macrophages, and neutrophils in formalin-fixed, paraffin-embedded tumor tissues isolated from these patients. Tumor immune-microenvironmental features and patient survival stratified by CLDN18.2 expression were analyzed using two independent-sample t-tests and log-rank tests, respectively. We considered moderate-to-strong CLDN18.2 expression ≥ 40% of tumor cells as the cut-off for positivity. The proportion of CD8+PD-1−, CD8+LAG-3−, and CD8+TIM-3− T cells was significantly higher in CLDN18.2-positive tumors than in negative tumors (0.039 vs. 0.026, P = 0.009; 0.050 vs.0.035, P = 0.024; 0.045 vs. 0.032, P = 0.038, respectively). In addition, the number of neutrophils (CD66b+) was higher in the CLDN18.2-positive group than in the negative group (0.081 vs. 0.055, P = 0.031, respectively), while the rates of M1 (CD68+CD163−HLA-DR+), M2 macrophages (CD68+CD163+HLA-DR−), and B cells (CD20+) were comparable between the CLDN18.2-positive and negative groups. The average numbers of CD8+PD-1−, CD8+LAG-3−, and CD8+TIM-3−T cells surrounding tumor cells within a 20-μm range were higher in CLDN18.2-positive tumors than in the CLDN18.2-negative tumors (0.16 vs. 0.09, P = 0.011; 0.20 vs. 0.12, P = 0.029; 0.18 vs. 0.12, P = 0.047, respectively). In addition, in the CLDN18.2-positive group, tumor cells surrounded by CD8+PD-1−, CD8+LAG-3− T cells, or M1 macrophages within a 20-μm range accounted for a higher proportion of all tumor cells than those in the CLDN18.2-negative group (10.79% vs. 6.60%, P = 0.015; 12.68% vs. 8.70%, P = 0.049; 9.08% vs. 6.56%, P = 0.033, respectively). These findings suggest that CLDN18.2-positive GC harbors complex immune-microenvironmental features. Additionally, CLDN18.2-positive group had shorter OS and irOS than CLDN18.2-negative group (median OS: 23.33 vs.36.6 months, P < 0.001; median irOS: 10.03 vs. 20.13 months, P = 0.044, respectively). CLDN18.2-positive GC displayed unique immune-microenvironmental characteristics, which is of great significance for the development of CLDN18.2-targeted therapies. However, the impact of CLDN18.2-related microenvironmental features on prognosis requires further investigation. The online version contains supplementary material available at 10.1186/s12916-022-02421-1.
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