Myc Cooperates with Ras by Programming Inflammation and Immune Suppression.
Myc Cooperates with Ras by Programming Inflammation and Immune Suppression.
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DOI：
10.1016/j.cell.2017.11.013
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发表时间：
2017-11-30
期刊：
影响因子：
64.5
通讯作者：
Evan GI
中科院分区：
文献类型：
--
作者：
Kortlever RM;Sodir NM;Wilson CH;Burkhart DL;Pellegrinet L;Brown Swigart L;Littlewood TD;Evan GI
两种癌基因KRas和Myc合作驱动肿瘤发生，但其机制仍不清楚。在KRasG 12 D驱动的腺瘤的小鼠肺模型中，我们发现Myc的共激活驱动了以高度炎症、血管生成和免疫抑制基质为标志的高度增殖和侵袭性腺癌的立即转变。我们确定上皮来源的信号分子CCL 9和IL-23作为基质重编程的主要指示信号。CCL 9介导巨噬细胞的募集、血管生成以及T和B细胞的PD-L1依赖性排出。IL-23协调适应性T和B细胞以及先天免疫NK细胞的排除。CCL 9和IL-23的共阻断消除Myc诱导的肿瘤进展。随后在已建立的腺癌中Myc的失活会触发所有间质变化和肿瘤消退的立即逆转，这不依赖于CD 4 + CD 8 + T细胞，但在很大程度上依赖于返回的NK细胞。我们发现Myc广泛地编程了一种免疫抑制基质，这是肿瘤进展所必需的。Myc和Ras通过肿瘤微环境在体内合作Myc直接编程血管生成、炎症和免疫抑制IL-23和CCL 9是Myc驱动的肺癌发生的细胞非自主效应物Myc驱动的肿瘤生长和维持依赖于免疫抑制致癌Myc活性协调免疫抑制性肿瘤微环境。
The two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRasG12D-driven adenomas, we find that co-activation of Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. We identify epithelial-derived signaling molecules CCL9 and IL-23 as the principal instructing signals for stromal reprogramming. CCL9 mediates recruitment of macrophages, angiogenesis, and PD-L1-dependent expulsion of T and B cells. IL-23 orchestrates exclusion of adaptive T and B cells and innate immune NK cells. Co-blockade of both CCL9 and IL-23 abrogates Myc-induced tumor progression. Subsequent deactivation of Myc in established adenocarcinomas triggers immediate reversal of all stromal changes and tumor regression, which are independent of CD4+CD8+ T cells but substantially dependent on returning NK cells. We show that Myc extensively programs an immune suppressive stroma that is obligatory for tumor progression. Myc and Ras cooperate in vivo through the tumor microenvironment Myc directly programs angiogenesis, inflammation, and immune suppression IL-23 and CCL9 are cell non-autonomous effectors of Myc-driven lung carcinogenesis Myc-driven tumor growth and maintenance depend on immune suppression Oncogenic Myc activity orchestrates an immune suppressive tumor microenvironment.
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DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
32.4
作者：
Joshi NS;Akama-Garren EH;Lu Y;Lee DY;Chang GP;Li A;DuPage M;Tammela T;Kerper NR;Farago AF;Robbins R;Crowley DM;Bronson RT;Jacks T
通讯作者：
Jacks T
影响因子：
8
作者：
Ji, H;Houghton, AM;Wong, KK
通讯作者：
Wong, KK
影响因子：
30.8
作者：
Christophorou, MA;Martin-Zanca, D;Evan, GI
通讯作者：
Evan, GI
影响因子：
7.3
作者：
Igarashi T;Teramoto K;Ishida M;Hanaoka J;Daigo Y
通讯作者：
Daigo Y