Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.
Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.
复制标题
种系DNA复制修复缺乏儿童对PD-1抑制反应的基因组预测指标。
DOI：
10.1038/s41591-021-01581-6
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发表时间：
2022-01
期刊：
影响因子：
82.9
通讯作者：
Tabori U
中科院分区：
文献类型：
--
作者：
Das A;Sudhaman S;Morgenstern D;Coblentz A;Chung J;Stone SC;Alsafwani N;Liu ZA;Karsaneh OAA;Soleimani S;Ladany H;Chen D;Zatzman M;Cabric V;Nobre L;Bianchi V;Edwards M;Sambira Nahum LC;Ercan AB;Nabbi A;Constantini S;Dvir R;Yalon-Oren M;Campino GA;Caspi S;Larouche V;Reddy A;Osborn M;Mason G;Lindhorst S;Bronsema A;Magimairajan V;Opocher E;De Mola RL;Sabel M;Frojd C;Sumerauer D;Samuel D;Cole K;Chiaravalli S;Massimino M;Tomboc P;Ziegler DS;George B;Van Damme A;Hijiya N;Gass D;McGee RB;Mordechai O;Bowers DC;Laetsch TW;Lossos A;Blumenthal DT;Sarosiek T;Yen LY;Knipstein J;Bendel A;Hoffman LM;Luna-Fineman S;Zimmermann S;Scheers I;Nichols KE;Zapotocky M;Hansford JR;Maris JM;Dirks P;Taylor MD;Kulkarni AV;Shroff M;Tsang DS;Villani A;Xu W;Aronson M;Durno C;Shlien A;Malkin D;Getz G;Maruvka YE;Ohashi PS;Hawkins C;Pugh TJ;Bouffet E;Tabori U
由生殖系DNA错配修复缺陷或聚合酶校对缺陷（MMRD和PPD）引起的儿童癌症在人类中具有最高的突变和微卫星插入-缺失（MS-indel）负担。MMRD和PPD癌症通常是致命的，这是由于对化学辐射的固有抗性。虽然免疫检查点抑制剂（ICI）在以前的研究中未能使儿童受益，但我们假设MMRD和PPD引起的超突变将改善这些患者ICI治疗后的结局。使用国际联盟注册研究，我们报告了ICI治疗38例患者的45例进行性或复发性肿瘤。在大多数患者中观察到持久的客观缓解，最终3年生存率为41.4%。高突变负荷预测富集组合MMRD + PPD的超超突变癌症（>100个突变/Mb）的应答，而MS-插入缺失预测具有较低突变负荷（10-100个突变/Mb）的MMRD肿瘤中的应答。此外，这两种机制都与增加的免疫浸润有关，即使在“免疫冷”肿瘤如胶质瘤中，也有助于有利的反应。假性进展（复发）很常见，与肿瘤微环境和全身的免疫激活相关。此外，继续ICI治疗的发作患者获得了持久的缓解。这项研究证明了先前不知道对ICI治疗有反应的肿瘤患者的生存率提高，包括中枢神经系统和同步癌症，并确定了突变负荷和MS-插入缺失在预测对免疫治疗的持续反应中的双重作用。超突变和微卫星负荷决定了患有生殖系DNA复制修复缺陷所致难治性癌症的儿童和年轻人在PD-1阻断后的反应和长期生存。
Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.
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影响因子：
16.6
作者：
Gromeier M;Brown MC;Zhang G;Lin X;Chen Y;Wei Z;Beaubier N;Yan H;He Y;Desjardins A;Herndon JE 2nd;Varn FS;Verhaak RG;Zhao J;Bolognesi DP;Friedman AH;Friedman HS;McSherry F;Muscat AM;Lipp ES;Nair SK;Khasraw M;Peters KB;Randazzo D;Sampson JH;McLendon RE;Bigner DD;Ashley DM
通讯作者：
Ashley DM
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
45.3
作者：
Azad, Nilofer S.;Gray, Robert J.;Flaherty, Keith T.
通讯作者：
Flaherty, Keith T.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.1706689114
发表时间：
2017-09-19
影响因子：
11.1
作者：
Antonios, Joseph P.;Soto, Horacio;Prins, Robert M.
通讯作者：
Prins, Robert M.