Vasquez Juan C, Huttner Anita, Zhang Lin, Marks Asher, Chan Amy, Baehring Joachim M, Kahle Kristopher T, Dhodapkar Kavita M
Department of Pediatrics, Yale School of Medicine, 333 Cedar Street, LMP 2073, New Haven, CT, 06510, USA.
Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
J Neurooncol. 2017 Aug;134(1):41-53. doi: 10.1007/s11060-017-2515-8. Epub 2017 Jun 15.
Therapies targeting immune checkpoints are effective in tumors with a high mutation burden that express multiple neo-antigens. However, glial tumors including those seen in children carry fewer mutations and there is an unmet need to identify new antigenic targets of anti-tumor immunity. SOX2 is an embryonal stem cell antigen implicated in the biology of glioma initiating cells. Expression of SOX2 by pediatric glial tumors and the capacity of the immune system in these patients to recognize SOX2 has not been previously studied. We examined the expression of SOX2 on archived paraffin-embedded tissue from pediatric glial tumors. The presence of T-cell immunity to SOX2 was examined in both blood and tumor-infiltrating T-cells in children and young adults with glioma. The nature of tumor-infiltrating immune cells was analyzed with a 37-marker panel using single-cell mass cytometry. SOX2 is expressed by tumor cells but not surrounding normal tissue in pediatric gliomas of all grades. T-cells against this antigen can be detected in blood and tumor tissue in glioma patients. Glial tumors are enriched for CD8/CD4 T-cells with tissue resident memory (T; CD45RO, CD69, CCR7) phenotype, which co-express multiple inhibitory checkpoints including PD-1, PD-L1 and TIGIT. Tumors also contain natural killer cells with reduced expression of lytic granzyme. Our data demonstrate immunogenicity of SOX2, which is specifically overexpressed on pediatric glial tumor cells. Harnessing tumor immunity in glioma will likely require the combined targeting of multiple inhibitory checkpoints.
针对免疫检查点的疗法在具有高突变负荷且表达多种新抗原的肿瘤中有效。然而，包括儿童期出现的胶质瘤在内的胶质肿瘤携带的突变较少，因此迫切需要确定抗肿瘤免疫的新抗原靶点。SOX2是一种胚胎干细胞抗原，与胶质瘤起始细胞的生物学特性有关。此前尚未研究过小儿胶质肿瘤中SOX2的表达情况以及这些患者免疫系统识别SOX2的能力。我们检测了小儿胶质肿瘤存档石蜡包埋组织中SOX2的表达情况。在患有胶质瘤的儿童和年轻成人的血液和肿瘤浸润性T细胞中检测了针对SOX2的T细胞免疫情况。使用单细胞质谱流式细胞术，通过一个包含37种标志物的组合对肿瘤浸润免疫细胞的性质进行了分析。在所有级别的小儿胶质瘤中，肿瘤细胞表达SOX2，而周围正常组织不表达。在胶质瘤患者的血液和肿瘤组织中可以检测到针对这种抗原的T细胞。胶质肿瘤富含具有组织驻留记忆（T；CD45RO、CD69、CCR7）表型的CD8/CD4 T细胞，这些细胞共表达包括PD-1、PD-L1和TIGIT在内的多种抑制性检查点。肿瘤中还含有溶细胞颗粒酶表达降低的自然杀伤细胞。我们的数据证明了SOX2的免疫原性，SOX2在小儿胶质肿瘤细胞上特异性过表达。在胶质瘤中利用肿瘤免疫可能需要联合靶向多个抑制性检查点。
