Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Front Immunol. 2020 Aug 20;11:1819. doi: 10.3389/fimmu.2020.01819. eCollection 2020.
Papillary renal cell carcinoma (PRCC) is a rare entity in children with no established therapy protocols for advanced diseases. Immunotherapy is emerging as an important therapeutic tool for childhood cancer. Tumor cells can be recognized and killed by conventional and unconventional T cells. Unconventional T cells are able to recognize lipid antigens presented via CD1 molecules independently from major histocompatibility complex, which offers new alternatives for cancer immunotherapies. The nature of those lipids is largely unknown and α-galactosylceramide is currently used as a synthetic model antigen. In this work, we analyzed infiltrating lymphocytes of two pediatric PRCCs using flow cytometry, immunohistochemistry and qRT-PCR. Moreover, we analyzed the CD1d expression within both tumors. Tumor lipids of PRCC samples and three normal kidney samples were fractionated and the recognition of tumor own lipid fractions by unconventional T cells was analyzed in an assay. We identified infiltrating lymphocytes including γδ T cells and iNKT cells, as well as CD1d expression in both samples. One lipid fraction, containing ceramides and monoacylglycerides amongst others, was able to induce the proliferation of iNKT cells isolated from peripheral blood mononuclear cells (PBMCs) of healthy donors and of one matched PRCC patient. Furthermore, CD1d tetramer stainings revealed that a subset of iNKT cells is able to bind lipids being present in fraction 2 via CD1d. We conclude that PRCCs are infiltrated by conventional and unconventional T cells and express CD1d. Moreover, certain lipids, present in pediatric PRCC, are able to stimulate unconventional T cells. Manipulating these lipids and T cells may open new strategies for therapy of pediatric PRCCs.
乳头状肾细胞癌 (PRCC) 在儿童中较为罕见，尚无针对晚期疾病的既定治疗方案。免疫疗法作为一种重要的儿童癌症治疗手段正在兴起。常规和非常规 T 细胞能够识别和杀伤肿瘤细胞。非常规 T 细胞能够通过 CD1 分子识别独立于主要组织相容性复合体的脂质抗原，为癌症免疫疗法提供了新的选择。这些脂质的性质在很大程度上尚不清楚，目前α-半乳糖神经酰胺被用作合成模型抗原。在这项工作中，我们使用流式细胞术、免疫组织化学和 qRT-PCR 分析了两例儿科 PRCC 的浸润淋巴细胞。此外，我们还分析了这两种肿瘤的 CD1d 表达情况。对 PRCC 样本和三个正常肾脏样本的肿瘤脂质进行了分级，并在体外分析了非常规 T 细胞对肿瘤自身脂质分级的识别。我们鉴定了浸润淋巴细胞，包括γδ T 细胞和 iNKT 细胞，以及两个样本中的 CD1d 表达。一个含有神经酰胺和单酰基甘油等的脂质分级能够诱导来自健康供体和一个匹配的 PRCC 患者外周血单核细胞 (PBMC) 的 iNKT 细胞的增殖。此外，CD1d 四聚体染色显示，一组 iNKT 细胞能够通过 CD1d 结合存在于分级 2 中的脂质。我们得出结论，PRCC 被常规和非常规 T 细胞浸润，并表达 CD1d。此外，儿科 PRCC 中存在的某些脂质能够刺激非常规 T 细胞。操纵这些脂质和 T 细胞可能为儿科 PRCC 的治疗开辟新的策略。
