Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance.
Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance.
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DOI：
10.1016/j.ccell.2020.12.023
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发表时间：
2021-04-12
期刊：
影响因子：
50.3
通讯作者：
Zou W
中科院分区：
文献类型：
--
作者：
Lin H;Kryczek I;Li S;Green MD;Ali A;Hamasha R;Wei S;Vatan L;Szeliga W;Grove S;Li X;Li J;Wang W;Yan Y;Choi JE;Li G;Bian Y;Xu Y;Zhou J;Yu J;Xia H;Wang W;Alva A;Chinnaiyan AM;Cieslik M;Zou W
免疫疗法在一小部分癌症患者中诱导持久的临床反应。然而，治疗耐药性对目前的免疫疗法构成了重大挑战。在这里，我们发现肿瘤斯坦钙素1 （STC1）的表达与免疫治疗疗效相关，并与不同癌症类型的患者生存呈负相关。在小鼠肿瘤模型中，功能获得和功能丧失实验表明，肿瘤STC1支持肿瘤进展，并使肿瘤抵抗检查点阻断。在机制上，肿瘤STC1与钙网蛋白（CRT）相互作用，这是一种“吃我”信号，并最大限度地减少CRT膜暴露-从而取消抗原呈递细胞（APCs），包括巨噬细胞和树突状细胞的膜CRT定向吞噬。因此，这损害了APC抗原呈递和T细胞活化的能力。因此，肿瘤STC1抑制APC吞噬，有助于肿瘤免疫逃避和免疫治疗抵抗。我们认为STC1是一个以前未被发现的吞噬检查点，靶向STC1及其与CRT的相互作用可能对癌症免疫治疗敏感。Lin等人证明肿瘤史坦钙素-1作为细胞内“吃我”信号阻滞剂，通过捕获钙钙蛋白并损害APC吞噬和T细胞活化。肿瘤斯坦钙素-1与免疫治疗疗效和患者生存率呈负相关。
Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current immunotherapies. Here, we identify that expression of tumor stanniocalcin 1 (STC1) correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types. Gain- and loss- of-function experiments demonstrate that tumor STC1 supports tumor progression and enables tumor resistance to checkpoint blockade in murine tumor models. Mechanistically, tumor STC1 interacts with calreticulin (CRT), an “eat-me” signal, and minimizes CRT membrane exposure - thereby abrogating membrane CRT-directed phagocytosis by antigen-presenting-cells (APCs), including macrophages and dendritic cells. Consequently, this impairs APC capacity of antigen presentation and T cell activation. Thus, tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance. We suggest that STC1 is a previously unappreciated phagocytosis checkpoint and targeting STC1 and its interaction with CRT may sensitize to cancer immunotherapy. Lin et al. demonstrate tumor stanniocalcin-1 functions as an intracellular “eat-me” signal blocker by trapping calreticulin and impairs APC phagocytosis and T cell activation. Tumor stanniocalcin-1 negatively correlates with immunotherapy efficacy and patient survival.
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影响因子：
64.8
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
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期刊：
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影响因子：
64.5
作者：
Majeti R;Chao MP;Alizadeh AA;Pang WW;Jaiswal S;Gibbs KD Jr;van Rooijen N;Weissman IL
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DOI：
10.1038/s41577-019-0218-4
发表时间：
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期刊：
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影响因子：
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