Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.
Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.
Cancer Immunol Res. 2023 Jan 3;11(1):20-37. doi: 10.1158/2326-6066.CIR-22-0098.
The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDCs localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity.
中枢神经系统 (CNS) 抗原呈递细胞 (APC) 启动抗肿瘤 CD8+ T 细胞反应的机制仍未确定。在身体的其他部位，传统树突状细胞 1 (cDC1) 发挥了这一作用。然而，静息状态下的脑实质 cDC1 极为罕见；cDC 定位于脉络丛和硬脑膜。因此，cDC1 是否在肿瘤环境中发挥作用，呈递源自实质来源的抗原仍不得而知。通过使用临床前胶质母细胞瘤 (GBM) 模型和 cDC1 缺陷小鼠，我们探索了 cDC1 在中枢神经系统抗肿瘤免疫中的目前未知作用。我们确定，除了浸润脑肿瘤实质本身外，cDC1 还能对脑肿瘤产生新抗原特异性 CD8+ T 细胞，并介导检查点阻断诱导的生存获益。我们观察到，从肿瘤、硬脑膜和中枢神经系统引流的颈淋巴结中分离出的 cDC，包括 cDC1，携带可追踪的荧光肿瘤抗原。在患者样本中，我们观察到几个 APC 亚群（包括 CD141+ cDC1 等效物）浸润胶质母细胞瘤、脑膜瘤和硬脑膜。在这些相同的 APC 亚群中，我们发现了 5-氨基乙酰丙酸的一种肿瘤特异性荧光代谢物，它在荧光引导的 GBM 切除过程中荧光标记肿瘤细胞。这些数据共同阐明了 cDC1 的特殊行为，并表明 cDC1 在中枢神经系统抗肿瘤免疫中发挥着重要作用。
