TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory.
TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory.
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DOI：
10.1016/j.ccell.2023.09.001
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发表时间：
2023-11-13
期刊：
影响因子：
50.3
通讯作者：
Alonso, Marta M.
中科院分区：
文献类型：
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作者：
Ausejo-Mauleon, Iker;Labiano, Sara;de la Nava, Daniel;Laspidea, Virginia;Zalacain, Marta;Marrodan, Lucia;Garcia-Moure, Marc;Gonzalez-Huarriz, Marisol;Hervas-Corpion, Irati;Dhandapani, Laasya;Vicent, Silvestre;Collantes, Maria;Penuelas, Ivan;Becher, Oren J.;Filbin, Mariella G.;Jiang, Li;Labelle, Jenna;de Biagi-Junior, Carlos A. O.;Nazarian, Javad;Laternser, Sandra;Phoenix, Timothy N.;van der Lugt, Jasper;Kranendonk, Mariette;Hoogendijk, Raoull;Mueller, Sabine;De Andrea, Carlos;Anderson, Ana C.;Guruceaga, Elizabeth;Koschmann, Carl;Yadav, Viveka Nand;Perez-Larraya, Jaime Gallego;Patino-Garcia, Ana;Pastor, Fernando;Alonso, Marta M.
弥漫性桥脑胶质瘤是一种侵袭性脑干肿瘤，是儿童肿瘤相关死亡的主要原因。迄今为止，这些肿瘤仍然无法治愈，强调了对有效治疗的需求。在这项研究中，我们证明了免疫检查点TIM-3（HAVCR 2）在DIPG中的肿瘤细胞和微环境细胞（主要是小胶质细胞和巨噬细胞）中高度表达。我们发现，在DIPG的同基因模型中抑制TIM-3可降低存活率，并产生无疾病的长期存活者，这些存活者具有免疫记忆。这种抗肿瘤作用是由肿瘤细胞中TIM-3抑制的直接作用、几种免疫细胞群的协调作用以及趋化因子/细胞因子的分泌驱动的，所述趋化因子/细胞因子产生有利于强效抗肿瘤免疫应答的促炎性肿瘤微环境。这项工作揭示了TIM-3作为DIPG的真正靶点，并支持其临床转化。TIM-3表达在DIPG患者的TME和肿瘤细胞中上调。TIM-3在DIPG肿瘤细胞增殖和肿瘤发生中起关键作用。TIM-3阻断增强小胶质细胞和CD 8 + T细胞功能，TIM-3阻断诱导持久的记忆应答，这通过肿瘤根除Ausejo-Mauleon et al.证明TIM-3是在DIPG肿瘤细胞和免疫微环境中高度表达的分子，并且由于DIPG肿瘤微环境通过小胶质细胞和CD 8 + T细胞活化转化为促炎表型，其阻断触发了有效的免疫应答，促进了抗胶质瘤应答和持久的免疫记忆。
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory. This antitumor effect is driven by the direct effect of TIM-3 inhibition in tumor cells, the coordinated action of several immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. This work uncovers TIM-3 as a bona fide target in DIPG and supports its clinical translation. TIM-3 expression is upregulated in the TME and tumor cells of DIPG patients TIM-3 plays a critical role in DIPG tumor cells proliferation and tumorigenesis TIM-3 blockade enhances microglia and CD8+ T cell function TIM-3 blockade induces a durable memory response, evidenced by tumor eradication Ausejo-Mauleon et al. demonstrate that TIM-3 is a highly expressed molecule in DIPG tumor cells and immune microenvironment, and its blockade triggers a potent immune response due to the conversion of the DIPG tumor microenvironment to a proinflammatory phenotype through microglia and CD8+ T cell activation, promoting an anti-glioma response and durable immunological memory.
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阻断 TIM3 可通过减少头颈癌中的调节性 T 细胞来缓解免疫抑制
DOI：
10.1186/s13046-018-0713-7
发表时间：
2018-03-05
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Liu JF;Wu L;Yang LL;Deng WW;Mao L;Wu H;Zhang WF;Sun ZJ
通讯作者：
Sun ZJ
影响因子：
11.2
作者：
Kim HS;Chang CY;Yoon HJ;Kim KS;Koh HS;Kim SS;Lee SJ;Kane LP;Park EJ
通讯作者：
Park EJ
利用4-1BB免疫检查点，以增强溶瘤病毒疗法的疗效，对弥漫性内在的蓬托神经胶质瘤。
影响因子：
8
作者：
Laspidea, Virginia;Puigdelloses, Montserrat;Labiano, Sara;Marrodan, Lucia;Garcia-Moure, Marc;Zalacain, Marta;Gonzalez-Huarriz, Marisol;Martinez-Velez, Naiara;Ausejo-Mauleon, Iker;de la Nava, Daniel;Herrador-Canete, Guillermo;Marco-Sanz, Javier;Guruceaga, Elisabeth;de Andrea, Carlos E.;Villalba, Maria;Becher, Oren;Squatrito, Massimo;Matia, Veronica;Gallego Perez-Larraya, Jaime;Patino-Garcia, Ana;Gupta, Sumit;Gomez-Manzano, Candelaria;Fueyo, Juan;Alonso, Marta M.
通讯作者：
Alonso, Marta M.
DOI：
10.1126/science.aao4750
发表时间：
2018-04-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Filbin MG;Tirosh I;Hovestadt V;Shaw ML;Escalante LE;Mathewson ND;Neftel C;Frank N;Pelton K;Hebert CM;Haberler C;Yizhak K;Gojo J;Egervari K;Mount C;van Galen P;Bonal DM;Nguyen QD;Beck A;Sinai C;Czech T;Dorfer C;Goumnerova L;Lavarino C;Carcaboso AM;Mora J;Mylvaganam R;Luo CC;Peyrl A;Popović M;Azizi A;Batchelor TT;Frosch MP;Martinez-Lage M;Kieran MW;Bandopadhayay P;Beroukhim R;Fritsch G;Getz G;Rozenblatt-Rosen O;Wucherpfennig KW;Louis DN;Monje M;Slavc I;Ligon KL;Golub TR;Regev A;Bernstein BE;Suvà ML
通讯作者：
Suvà ML
影响因子：
3.6
作者：
Di Ruscio, Valentina;Del Baldo, Giada;Fabozzi, Francesco;Vinci, Maria;Cacchione, Antonella;de Billy, Emmanuel;Megaro, Giacomina;Carai, Andrea;Mastronuzzi, Angela
通讯作者：
Mastronuzzi, Angela