Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade.
Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade.
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DOI：
10.1016/j.immuni.2020.10.020
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发表时间：
2020-12-15
期刊：
影响因子：
32.4
通讯作者：
Zelenay S
中科院分区：
文献类型：
--
作者：
Bonavita E;Bromley CP;Jonsson G;Pelly VS;Sahoo S;Walwyn-Brown K;Mensurado S;Moeini A;Flanagan E;Bell CR;Chiang SC;Chikkanna-Gowda CP;Rogers N;Silva-Santos B;Jaillon S;Mantovani A;Reis e Sousa C;Guerra N;Davis DM;Zelenay S
炎症可以支持或抑制癌症的进展和对治疗的反应。在这里，我们通过深入分析与小鼠免疫依赖性控制相关的炎症性肿瘤微环境（TMEs）来寻找癌症抑制性炎症的主要调节因子。我们发现，早期肿瘤内产生干扰素γ (IFN-γ)的自然杀伤（NK）细胞的积累诱导了TME的深度重塑，并释放了细胞毒性T细胞（CTL）介导的肿瘤根除。从机制上讲，肿瘤源性前列腺素E2 （PGE2）选择性作用于NK细胞上的EP2和EP4受体，阻碍TME开关，使免疫逃逸。对人类癌症患者数据集的分析揭示了不同的炎性TME表型，类似于小鼠癌症免疫控制与逃逸相关的表型。这使我们能够生成一种基因表达特征，该特征整合了对抗炎症因子，并预测了患者的生存和对免疫检查点封锁的反应。我们的研究结果确定了与癌症免疫控制相关的肿瘤炎症环境的特征，并建立了预测免疫治疗结果的策略。NK细胞驱动t细胞炎症肿瘤的广泛炎症重塑特征PGE2作用于NK细胞上的EP2和EP4阻止TME开关使免疫逃逸在许多人类癌症类型中发现的相反的炎症谱具有预后价值一个特征捕获促肿瘤和抗肿瘤因子预测免疫治疗的反应炎症可以促进或抑制癌症。Bonavita等人在小鼠模型中发现NK细胞是T细胞炎症的主要协调者，并设计了一种炎症特征，预测多种恶性肿瘤患者的生存和对免疫治疗的反应。
Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes. NK cells drive broad inflammatory remodeling characteristic of T-cell-inflamed tumors PGE2 acting on EP2 and EP4 on NK cells prevents the TME switch enabling immune escape Opposing inflammatory profiles found in many human cancer types have prognostic value A signature capturing pro- and anti-tumor factors predicts response to immunotherapy Inflammation can fuel or suppress cancer. Bonavita et al. identify NK cells as primary orchestrators of T cell inflammation in murine models and devise an inflammatory signature that predicts patient survival and response to immunotherapy in multiple malignancies.
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影响因子：
28.2
作者：
Chen PL;Roh W;Reuben A;Cooper ZA;Spencer CN;Prieto PA;Miller JP;Bassett RL;Gopalakrishnan V;Wani K;De Macedo MP;Austin-Breneman JL;Jiang H;Chang Q;Reddy SM;Chen WS;Tetzlaff MT;Broaddus RJ;Davies MA;Gershenwald JE;Haydu L;Lazar AJ;Patel SP;Hwu P;Hwu WJ;Diab A;Glitza IC;Woodman SE;Vence LM;Wistuba II;Amaria RN;Kwong LN;Prieto V;Davis RE;Ma W;Overwijk WW;Sharpe AH;Hu J;Futreal PA;Blando J;Sharma P;Allison JP;Chin L;Wargo JA
通讯作者：
Wargo JA
影响因子：
10.9
作者：
Danaher P;Warren S;Lu R;Samayoa J;Sullivan A;Pekker I;Wallden B;Marincola FM;Cesano A
通讯作者：
Cesano A
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF
影响因子：
64.5
作者：
André P;Denis C;Soulas C;Bourbon-Caillet C;Lopez J;Arnoux T;Bléry M;Bonnafous C;Gauthier L;Morel A;Rossi B;Remark R;Breso V;Bonnet E;Habif G;Guia S;Lalanne AI;Hoffmann C;Lantz O;Fayette J;Boyer-Chammard A;Zerbib R;Dodion P;Ghadially H;Jure-Kunkel M;Morel Y;Herbst R;Narni-Mancinelli E;Cohen RB;Vivier E
通讯作者：
Vivier E