肿瘤细胞治疗研究
英文原题：Spatial organization of heterogeneous immunotherapy target antigen expression in high-grade glioma.
Spatial organization of heterogeneous immunotherapy target antigen expression in high-grade glioma.
高级别（WHO III-IV 级）胶质瘤仍然是人类最致命的癌症之一。
高级别胶质瘤（WHO Ⅲ～Ⅳ级）仍是致死率最高的人类癌症之一。采用靶向肿瘤的嵌合抗原受体（CAR）T细胞进行过继转移，已显示出有希望的抗肿瘤活性信号，但多数患者仍难以获得客观临床缓解。有效免疫治疗面临的重大挑战之一是这类肿瘤结构高度异质，包括靶抗原表达水平和分布范围差异巨大；这种差异既存在于同一肿瘤内部，也存在于不同患者之间。为更详细了解患者肿瘤中的免疫治疗靶抗原，研究者在一组43名患者的肿瘤样本中，以单细胞分辨率免疫化学绘制了3种具有临床相关性的靶点：IL13Rα2、HER2和EGFR。结果显示，同一肿瘤样本内这些抗原的表达并非随机或均一分布，而是在肿瘤细胞区域形成局部细胞簇；簇内细胞表型相似，反映了尚未充分理解的肿瘤细胞及其微环境特性。值得注意的是，高抗原表达细胞簇在组织区域内也并非彼此独立分布。例如，在肿瘤细胞密集区域，IL13Rα2和HER2高表达簇与EGFR高表达簇呈互补分布；而在假栅栏状坏死区域，IL13Rα2和HER2（而非EGFR）的表达似乎反映了肿瘤细胞围绕缺氧核心的放射状排列。其他影响免疫治疗靶抗原表达的结构特征仍待阐明。高级别胶质瘤中这种有组织但异质的抗原表达分布，非常容易导致抗原逃逸；联合靶向多个抗原是常被提出的潜在缓解策略。深入了解患者肿瘤内部及患者之间抗原表达情况，将有助于优化联合免疫治疗。本文观察结果最直接的临床启示是，应考虑将野生型EGFR纳入靶抗原。
High-grade (WHO grades III-IV) glioma remains one of the most lethal human cancers. Adoptive transfer of tumor-targeting chimeric antigen receptor (CAR)-redirected T cells for high-grade glioma has revealed promising indications of anti-tumor activity, but objective clinical responses remain elusive for most patients. A significant challenge to effective immunotherapy is the highly heterogeneous structure of these tumors, including large variations in the magnitudes and distributions of target antigen expression, observed both within individual tumors and between patients. To obtain a more detailed understanding of immunotherapy target antigens within patient tumors, we immunochemically mapped at single cell resolution three clinically-relevant targets, IL13R 2, HER2 and EGFR, on tumor samples drawn from a 43-patient cohort. We observed that within individual tumor samples, expression of these antigens was neither random nor uniform, but rather that they mapped into local neighborhoods - phenotypically similar cells within regions of cellular tumor - reflecting not well understood properties of tumor cells and their milieu. Notably, tumor cell neighborhoods of high antigen expression were not arranged independently within regions. For example, in cellular tumor regions, neighborhoods of high IL13R 2 and HER2 expression appeared to be reciprocal to those of EGFR, while in areas of pseudopalisading necrosis, expression of IL13R 2 and HER2, but not EGFR, appeared to reflect the radial organization of tumor cells around hypoxic cores. Other structural features affecting expression of immunotherapy target antigens remain to be elucidated. This structured but heterogeneous organization of antigen expression in high grade glioma is highly permissive for antigen escape, and combinatorial antigen targeting is a commonly suggested potential mitigating strategy. Deeper understanding of antigen expression within and between patient tumors will enhance optimization of combination immunotherapies, the most immediate clinical application of the observations presented here being the importance of including (wild-type) EGFR as a target antigen.
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