Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine.
Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine.
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DOI：
10.1186/s13073-018-0605-7
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发表时间：
2018-11-29
期刊：
影响因子：
12.3
通讯作者：
Van Allen E
中科院分区：
文献类型：
--
作者：
Conway JR;Kofman E;Mo SS;Elmarakeby H;Van Allen E
免疫检查点阻断(ICB)疗法可以增强人体对肿瘤细胞的自然免疫反应，在治疗各种癌症方面显示出巨大的前景。目前，肿瘤突变负荷(TMB)和程序性死亡配体1(PD-L1)的表达是跨组织学评估癌症患者临床治疗的主要生物标志物。然而，广泛的反应表明，必须考虑每个患者肿瘤和免疫系统的特定分子和基因特征，以最大限度地提高治疗效果。在此，我们综述了PD-(L)1和细胞毒性T淋巴细胞相关抗原4(CTLA-4)治疗所涉及的各种生物学途径和新的生物标志物，包括肿瘤信号通路、人类白细胞抗原的变异性、突变和新抗原负荷、微生物组组成、内源性逆转录病毒(ERV)以及染色质重塑和DNA损伤修复机制的缺陷。我们还讨论了已观察到的几种赋予ICB抗性的机制，如失去磷酸酶和张力蛋白同源物，失去主要组织相容性复合体I/II的表达，以及吲哚胺2，3-双加氧酶1和转化生长因子ββ通路的激活。测试PD-(L)1或CTLA-4阻滞剂与这些通路的分子介质结合的临床试验正变得越来越常见，并有望改善治疗效果和反应。最终，这篇综述中强调的一些基因和分子机制可能会作为新的生物靶点或治疗脆弱性来改善患者的临床结果。
Immune checkpoint blockade (ICB) therapies, which potentiate the body’s natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient’s tumor and immune system must be considered to maximize treatment efficacy. Here, we review the various biological pathways and emerging biomarkers implicated in response to PD-(L)1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapies, including oncogenic signaling pathways, human leukocyte antigen (HLA) variability, mutation and neoantigen burden, microbiome composition, endogenous retroviruses (ERV), and deficiencies in chromatin remodeling and DNA damage repair (DDR) machinery. We also discuss several mechanisms that have been observed to confer resistance to ICB, such as loss of phosphatase and tensin homolog (PTEN), loss of major histocompatibility complex (MHC) I/II expression, and activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta (TGFβ) pathways. Clinical trials testing the combination of PD-(L)1 or CTLA-4 blockade with molecular mediators of these pathways are becoming more common and may hold promise for improving treatment efficacy and response. Ultimately, some of the genes and molecular mechanisms highlighted in this review may serve as novel biological targets or therapeutic vulnerabilities to improve clinical outcomes in patients.
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影响因子：
16.6
作者：
Dushyanthen S;Teo ZL;Caramia F;Savas P;Mintoff CP;Virassamy B;Henderson MA;Luen SJ;Mansour M;Kershaw MH;Trapani JA;Neeson PJ;Salgado R;McArthur GA;Balko JM;Beavis PA;Darcy PK;Loi S
通讯作者：
Loi S
影响因子：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira
癌症免疫疗法。树突状细胞疫苗增加了黑色素瘤新抗原特异性T细胞的广度和多样性。
DOI：
10.1126/science.aaa3828
发表时间：
2015-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Carreno BM;Magrini V;Becker-Hapak M;Kaabinejadian S;Hundal J;Petti AA;Ly A;Lie WR;Hildebrand WH;Mardis ER;Linette GP
通讯作者：
Linette GP
影响因子：
8.8
作者：
Abiko, K.;Matsumura, N.;Hamanishi, J.;Horikawa, N.;Murakami, R.;Yamaguchi, K.;Yoshioka, Y.;Baba, T.;Konishi, I.;Mandai, M.
通讯作者：
Mandai, M.
DOI：
10.1126/science.aar3593
发表时间：
2018-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cristescu R;Mogg R;Ayers M;Albright A;Murphy E;Yearley J;Sher X;Liu XQ;Lu H;Nebozhyn M;Zhang C;Lunceford JK;Joe A;Cheng J;Webber AL;Ibrahim N;Plimack ER;Ott PA;Seiwert TY;Ribas A;McClanahan TK;Tomassini JE;Loboda A;Kaufman D
通讯作者：
Kaufman D