肿瘤细胞治疗研究
英文原题：Multiplex immunohistochemistry defines the tumor immune microenvironment and immunotherapeutic outcome in CLDN18.2-positive gastric cancer.
CLDN18.2阳性GC显示出独特的免疫微环境特征，这对CLDN18.2靶向治疗的开发具有重要意义。然而，CLDN18.2相关微环境特征对预后的影响仍需进一步研究。
FAST研究确定claudin-18（CLDN18.2）是胃癌（GC）有前景的新治疗靶点。然而，CLDN18.2阳性GC的肿瘤免疫微环境和临床病理特征尚不清楚，这使得开发和优化CLDN18.2靶向治疗变得困难。
本研究纳入80例GC患者，其中60例接受了抗PD-1/PD-L1治疗。采用多重免疫组化（m-IHC）标记CD4/CD8/CD20/CD66b/CD68/CD163/PD-1/PD-L1/TIM-3/LAG-3/FoxP3/CTLA-4/HLA-DR/STING和CLDN18.2，以解析从这些患者分离的福尔马林固定、石蜡包埋肿瘤组织中T细胞、B细胞、巨噬细胞和中性粒细胞的比率及空间分布。分别采用两独立样本t检验和log-rank检验分析按CLDN18.2表达分层的肿瘤免疫微环境特征和患者生存。
我们将肿瘤细胞中CLDN18.2中度至强表达≥40%视为阳性的cut-off值。CLDN18.2阳性肿瘤中CD8 + PD-1 -、CD8 + LAG-3 - 和CD8 + 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，CLDN18.2阳性组的中性粒细胞（CD66b +）数量高于阴性组（分别为0.081 vs. 0.055，P = 0.031），而M1（CD68 + CD163 - HLA-DR +）、M2巨噬细胞（CD68 + CD163 + HLA-DR -）和B细胞（CD20 +）的比例在CLDN18.2阳性组和阴性组之间相当。在20-μm范围内，CLDN18.2阳性肿瘤周围CD8 + PD-1 -、CD8 + LAG-3 - 和CD8 + 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，20-μm范围内被CD8 + PD-1 -、CD8 + 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）。
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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