Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.

中文翻译：

---

肿瘤坏死因子克服了 p53 突变髓母细胞瘤的免疫逃避。


许多免疫疗法通过增强细胞毒性 T 细胞杀死肿瘤细胞的能力来发挥作用。杀伤取决于 T 细胞对肿瘤细胞上 I 类主要组织相容性复合体 (MHC-I) 蛋白呈递的抗原的识别。在这项研究中，我们发现缺乏 p53 肿瘤抑制因子的髓母细胞瘤不表达表面 MHC-I，因此对免疫排斥具有抵抗力。从机制上讲，这是因为 p53 调节肽转运蛋白 Tap1 和氨肽酶 Erap1 的表达，这是 MHC-I 运输到细胞表面所必需的。在体外，肿瘤坏死因子 (TNF) 或淋巴毒素-β 受体激动剂可以挽救 p53 突变肿瘤细胞上 Erap1、Tap1 和 MHC-I 的表达。在体内，低剂量的 TNF 可延长生存期，并与免疫检查点抑制剂协同作用，促进肿瘤排斥。这些研究确定 p53 是免疫逃避的关键调节因子，并表明 TNF 可用于增强肿瘤对免疫治疗的敏感性。