Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy.
Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy.
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DOI：
10.1016/j.cell.2020.10.045
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发表时间：
2020-11-25
期刊：
影响因子：
64.5
通讯作者：
Abdi R
中科院分区：
文献类型：
--
作者：
Jiang L;Wang YJ;Zhao J;Uehara M;Hou Q;Kasinath V;Ichimura T;Banouni N;Dai L;Li X;Greiner DL;Shultz LD;Zhang X;Sun ZJ;Curtin I;Vangos NE;Yeoh ZC;Geffken EA;Seo HS;Liu ZX;Heffron GJ;Shah K;Dhe-Paganon S;Abdi R
癌症疗法通过激发免疫反应直接或间接地杀死肿瘤，并已取得不同程度的成功。在这里，我们描述了一种控制癌症生长的范例，它基于直接杀死肿瘤和触发保护性免疫。丝氨酸蛋白酶抑制剂SerpinB9 （Sb9）的基因消融导致肿瘤细胞以颗粒酶B （GrB）依赖的方式死亡。sb9缺陷小鼠对肿瘤表现出保护性的基于T细胞的宿主免疫，这与肿瘤微环境（TME）中表达grb的免疫抑制细胞的减少有关。当肿瘤和宿主缺乏Sb9时，对肿瘤发展的保护作用最大。抑制Sb9的治疗效用被证明是通过控制肿瘤生长，导致小鼠的生存时间增加。我们的研究描述了一种分子靶点，它允许肿瘤消融、TME内干扰和免疫治疗在一种潜在的模式下结合。SerpinB9对肿瘤细胞存活和肿瘤微环境中免疫抑制细胞的存在很重要，在几种小鼠癌症模型中，SerpinB9的小分子抑制剂可以降低肿瘤生长并增加肿瘤免疫原性。
Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality. SerpinB9 is important for tumor cell survival and for the presence of immunosuppressive cells in the tumor microenvironment, and a small-molecule inhibitor of SerpinB9 can reduce tumor growth and increase tumor immunogenicity in several mouse models of cancer.
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影响因子：
4.1
作者：
Annand, RR;Dahlen, JR;Giegel, DA
通讯作者：
Giegel, DA
影响因子：
50.3
作者：
Barrett, Lindy E.;Granot, Zvi;Benezra, Robert
通讯作者：
Benezra, Robert
影响因子：
7.3
作者：
Kim MT;Harty JT
通讯作者：
Harty JT
DOI：
10.1186/s13046-016-0302-6
发表时间：
2016-02-02
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
D'Eliseo D;Di Rocco G;Loria R;Soddu S;Santoni A;Velotti F
通讯作者：
Velotti F
影响因子：
64.8
作者：
Huntington, JA;Read, RJ;Carrell, RW
通讯作者：
Carrell, RW