An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection.
An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection.
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DOI：
10.1007/s00262-017-2047-2
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Weiner LM
中科院分区：
文献类型：
--
作者：
Shuptrine CW;Ajina R;Fertig EJ;Jablonski SA;Kim Lyerly H;Hartman ZC;Weiner LM
癌症免疫检查点疗法的临床成功使得识别对抗肿瘤免疫应答的抗性机制变得重要。通过对单个基因或途径的研究，已经确定了许多耐药机制，从而将肿瘤微环境的复杂性解析成易于处理的片段。然而，这将新基因发现的潜力限制在体内免疫攻击。为了应对这一挑战，我们开发了一种无偏见的体内全基因组RNAi筛选平台，该平台利用免疫活性和免疫缺陷小鼠品系中的宿主免疫选择来选择调节体内免疫攻击敏感性的基于肿瘤细胞的基因。在同基因三阴性乳腺癌（TNBC）模型中利用这种方法，我们确定了709个选择性调节适应性抗肿瘤免疫的基因，并集中在5个影响最大的基因（CD47，TGFβ1，Sgpl1，Tex9和Pex14）。我们验证了这些基因在不同TNBC系中表达的免疫相关效应以及串联协同相互作用的机制。此外，我们证明了具有先前未知免疫功能的不同基因（Tex9和Pex14）对抗肿瘤免疫的影响。因此，这种创新的方法在多种环境中识别未知的肿瘤特异性免疫识别调节剂以揭示未来免疫疗法的新靶点方面具有实用性。
The clinical successes of immune checkpoint therapies for cancer make it important to identify mechanisms of resistance to anti-tumor immune responses. Numerous resistance mechanisms have been identified employing studies of single genes or pathways, thereby parsing the tumor microenvironment complexity into tractable pieces. However, this limits the potential for novel gene discovery to in vivo immune attack. To address this challenge, we developed an unbiased in vivo genome-wide RNAi screening platform that leverages host immune selection in strains of immunocompetent and immunodeficient mice to select for tumor cell-based genes that regulate in vivo sensitivity to immune attack. Utilizing this approach in a syngeneic Triple-Negative Breast Cancer (TNBC) model, we identified 709 genes that selectively regulated adaptive anti-tumor immunity, and focused on five genes (CD47, TGFβ1, Sgpl1, Tex9 and Pex14) with the greatest impact. We validated the mechanisms that underlie the immune-related effects of expression of these genes in different TNBC lines, as well as tandem synergistic interactions. Furthermore, we demonstrate the impact of different genes with previously unknown immune functions (Tex9 and Pex14) on anti-tumor immunity. Thus, this innovative approach has utility in identifying unknown tumor-specific regulators of immune recognition in multiple settings to reveal novel targets for future immunotherapies.
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影响因子：
82.9
作者：
Liu X;Pu Y;Cron K;Deng L;Kline J;Frazier WA;Xu H;Peng H;Fu YX;Xu MM
通讯作者：
Xu MM
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
4.7
作者：
Leto, Simonetta M.;Trusolino, Livio
通讯作者：
Trusolino, Livio
影响因子：
45.3
作者：
Lynch, Thomas J.;Bondarenko, Igor;Reck, Martin
通讯作者：
Reck, Martin
影响因子：
64.5
作者：
Albertini, M;Rehling, P;Kunau, WH
通讯作者：
Kunau, WH