Resistance to checkpoint blockade therapy through inactivation of antigen presentation.
Resistance to checkpoint blockade therapy through inactivation of antigen presentation.
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DOI：
10.1038/s41467-017-01062-w
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发表时间：
2017-10-26
影响因子：
16.6
通讯作者：
Hacohen N
中科院分区：
文献类型：
--
作者：
Sade-Feldman M;Jiao YJ;Chen JH;Rooney MS;Barzily-Rokni M;Eliane JP;Bjorgaard SL;Hammond MR;Vitzthum H;Blackmon SM;Frederick DT;Hazar-Rethinam M;Nadres BA;Van Seventer EE;Shukla SA;Yizhak K;Ray JP;Rosebrock D;Livitz D;Adalsteinsson V;Getz G;Duncan LM;Li B;Corcoran RB;Lawrence DP;Stemmer-Rachamimov A;Boland GM;Landau DA;Flaherty KT;Sullivan RJ;Hacohen N
免疫检查点阻断（CPB）治疗通常导致转移性黑色素瘤患者的反应延长，但对这些药物的原发性和获得性耐药的常见机制仍不完全，尚未在大型队列中得到验证。通过分析17例接受CPB治疗的转移性黑色素瘤患者的纵向肿瘤活检，我们观察到29.4%的进展性疾病患者的β 2-微球蛋白（B2 M）（MHC I类抗原呈递的重要组成部分）存在点突变、缺失或杂合性缺失（洛）。在分别用抗CTLA 4和抗PD 1治疗的两个独立的黑色素瘤患者队列中，我们发现B2 M洛在无应答者（~30%）中比应答者（~10%）富集三倍，并且与较差的总生存期相关。B2 M的两个拷贝的丢失仅在无应答者中发现。B2 M丢失可能是对靶向CTLA 4或PD 1的疗法的抗性的常见机制。对免疫检查点阻断的抵抗通常发生在治疗的患者中。在这里，作者证明B2 M损失是黑色素瘤患者对靶向CTLA 4或PD-1的治疗的原发性和获得性耐药的机制。
Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1. Resistance to immune-checkpoint blockade often occurs in treated patients. Here, the authors demonstrate that B2M loss is a mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1 in melanoma patients.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
DOI：
10.1109/tcbb.2013.2297113
发表时间：
2014-01-01
影响因子：
4.5
作者：
Amit, Mika;Backofen, Rolf;Will, Sebastian
通讯作者：
Will, Sebastian
影响因子：
6.4
作者：
Kloor, Matthias;Michel, Sara;Doeberitz, Magnus von Kriebel
通讯作者：
Doeberitz, Magnus von Kriebel
影响因子：
64.8
作者：
Berger, Michael F.;Hodis, Eran;Heffernan, Timothy P.;Deribe, Yonathan Lissanu;Lawrence, Michael S.;Protopopov, Alexei;Ivanova, Elena;Watson, Ian R.;Nickerson, Elizabeth;Ghosh, Papia;Zhang, Hailei;Zeid, Rhamy;Ren, Xiaojia;Cibulskis, Kristian;Sivachenko, Andrey Y.;Wagle, Nikhil;Sucker, Antje;Sougnez, Carrie;Onofrio, Robert;Ambrogio, Lauren;Auclair, Daniel;Fennell, Timothy;Carter, Scott L.;Drier, Yotam;Stojanov, Petar;Singer, Meredith A.;Voet, Douglas;Jing, Rui;Saksena, Gordon;Barretina, Jordi;Ramos, Alex H.;Pugh, Trevor J.;Stransky, Nicolas;Parkin, Melissa;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Wargo, Jennifer;Schadendorf, Dirk;Meyerson, Matthew;Gabriel, Stacey B.;Golub, Todd R.;Wagner, Stephan N.;Lander, Eric S.;Getz, Gad;Chin, Lynda;Garraway, Levi A.
通讯作者：
Garraway, Levi A.