Background/Objectives: The oncofetal membrane protein Claudin 6 (CLDN6) is an attractive target for T cell-based therapies. There is a lack of detailed analyses on the age-dependent expression of CLDN6 in normal tissues is lacking, which limits the expansion of CLDN6 CAR-T cell clinical trials to pediatric populations.Methods: We analyzed CLDN6 expression in extracranial solid tumors and normal tissues of children using RNA-sequencing data from over 500 pediatric solid tumor samples, qRT-PCR and immunohistochemistry (IHC) in more than 100 fresh-frozen tumor samples and, approximately, 250 formalin-fixed paraffin-embedded (FFPE) samples. We examined normal tissue expression via qRT-PCR in 32 different infant tissues and via IHC in roughly 290 tissues from donors across four age groups, as well as in fetal autopsy samples.Results: In fetal tissues, we detected CLDN6 expression primarily in the epithelial cells of several organs, including the skin, lungs, kidneys, intestinal tract, and pancreas, but not in undifferentiated blastemal cells. Postnatally, we found CLDN6-positive epithelial progenitors only during the first few weeks of life. In older-age groups, isolated clusters of CLDN6-positive progenitors were present, but in scarce quantities. In tumor tissues, we found strong and homogeneous CLDN6 expression in desmoplastic small round cell tumors and germ cell tumors. Wilms tumors demonstrated heterogeneous CLDN6 expression, notably absent in the blastemal component.Conclusions: These findings highlight an organ-specific presence of CLDN6-positive epithelial precursors that largely disappear in terminally differentiated epithelia within weeks after birth. Therefore, our data support CLDN6 as a viable therapeutic target in pediatric patients and justify their inclusion in basket studies for anti-CLDN6-based therapies.
背景/目的：癌胚膜蛋白Claudin 6（CLDN6）是基于T细胞疗法的一个有吸引力的靶点。目前缺乏对CLDN6在正常组织中年龄依赖性表达的详细分析，这限制了CLDN6 CAR-T细胞临床试验向儿科人群的扩展。方法：我们利用来自500多例儿童实体瘤样本的RNA测序数据、100多例新鲜冷冻肿瘤样本和约250例福尔马林固定石蜡包埋（FFPE）样本的qRT-PCR和免疫组织化学（IHC）分析，研究了儿童颅外实体瘤和正常组织中CLDN6的表达。我们通过qRT-PCR检测了32种不同婴儿组织的正常组织表达，并通过IHC检测了来自四个年龄组供体的约290个组织以及胎儿尸检样本中的表达。结果：在胎儿组织中，我们检测到CLDN6主要在多个器官的上皮细胞中表达，包括皮肤、肺、肾脏、肠道和胰腺，但在未分化的胚基细胞中未检测到表达。出生后，我们仅在生命最初几周内发现了CLDN6阳性的上皮祖细胞。在年龄较大的组别中，存在孤立的CLDN6阳性祖细胞簇，但数量稀少。在肿瘤组织中，我们在促结缔组织增生性小圆细胞肿瘤和生殖细胞肿瘤中发现了强且均匀的CLDN6表达。肾母细胞瘤表现出异质性的CLDN6表达，尤其在胚基成分中缺失。结论：这些发现突出了CLDN6阳性上皮前体细胞的器官特异性存在，这些细胞在出生后数周内基本在终末分化的上皮中消失。因此，我们的数据支持CLDN6作为儿科患者可行的治疗靶点，并为其纳入基于抗CLDN6疗法的篮式研究提供了依据。
肿瘤(癌症)患者之家