Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation
Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation
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自噬缺陷通过阻止生腱蛋白-C 降解促进三阴性乳腺癌对 T 细胞介导的细胞毒性的抵抗
DOI：
10.1038/s41467-020-17395-y
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发表时间：
2020-07-30
影响因子：
16.6
通讯作者：
Deng, Rong
中科院分区：
文献类型：
--
作者：
Li, Zhi-Ling;Zhang, Hai-Liang;Deng, Rong
大多数三阴性乳腺癌（TNBC）患者对T细胞介导的免疫疗法没有反应。不幸的是，分子决定因素仍然知之甚少。乳腺癌是一种与自噬缺陷有关的疾病。在这里，我们表明TNBC细胞中的自噬缺陷在体外和体内抑制T细胞介导的肿瘤杀伤。从机制上讲，我们将腱生蛋白-C确定为自噬缺陷介导的免疫抑制的候选者，其中腱生蛋白-C被Skp 2的Lys 63泛素化，特别是在Lys 942和Lys 1882处，从而促进其被p62识别并导致其选择性自噬降解。在TNBC患者中，高生腱蛋白-C表达与不良预后相关，并且与LC 3B表达和CD 8 +T细胞负相关。更重要的是，抑制自噬受损的TNBC细胞中的生腱蛋白-C使T细胞介导的肿瘤杀伤敏感，并改善单一抗PD 1/PDL 1疗法的抗肿瘤作用。我们的研究结果提供了一种潜在的策略，用于靶向TNBC与生腱蛋白-C阻断剂和免疫检查点抑制剂的组合。
Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8+T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.