Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.
Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.
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DOI：
10.1038/nature13988
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发表时间：
2014-11-27
期刊：
影响因子：
64.8
通讯作者：
Schreiber, Robert D.
中科院分区：
文献类型：
--
作者：
Gubin, Matthew M.;Zhang, Xiuli;Schuster, Heiko;Caron, Etienne;Ward, Jeffrey P.;Noguchi, Takuro;Ivanova, Yulia;Hundal, Jasreet;Arthur, Cora D.;Krebber, Willem-Jan;Mulder, Gwenn E.;Toebes, Mireille;Vesely, Matthew D.;Lam, Samuel S. K.;Korman, Alan J.;Allison, James P.;Freeman, Gordon J.;Sharpe, Arlene H.;Pearce, Erika L.;Schumacher, Ton N.;Aebersold, Ruedi;Rammensee, Hans-Georg;Melief, Cornelis J. M.;Mardis, Elaine R.;Gillanders, William E.;Artyomov, Maxim N.;Schreiber, Robert D.
免疫系统在决定发展中的癌症的命运中起着关键作用，不仅作为促进细胞转化、促进肿瘤生长和塑造肿瘤细胞免疫原性的肿瘤促进剂，而且作为破坏发展中的肿瘤或抑制其扩张的外源性肿瘤抑制剂。然而，临床上明显的癌症仍然出现在免疫功能正常的个体中，部分原因是癌症诱导的免疫抑制。在许多个体中，免疫抑制是由细胞毒性T淋巴细胞相关抗原-4（CTLA-4）和程序性死亡-1（PD-1）介导的，这两种免疫调节受体在T细胞上表达。靶向CTLA-4和/或PD-1（检查点阻断）的单克隆抗体（mAb）疗法已对不同恶性肿瘤患者产生了显著的临床获益（包括持久缓解）。然而，人们对作为检查点阻断免疫疗法激活的T细胞靶点的肿瘤抗原的身份以及这些抗原是否可用于产生高度肿瘤特异性的疫苗知之甚少。在本文中，我们使用基因组学和生物信息学方法来鉴定肿瘤特异性突变蛋白作为αPD-1和/或αCTLA-4治疗携带进行性生长肉瘤的小鼠后的主要类别的T细胞排斥抗原，并表明结合这些突变表位的治疗性合成长肽（SLP）疫苗诱导肿瘤排斥，而不是检查点阻断免疫治疗。然而，突变型肿瘤抗原特异性T细胞存在于进行性生长的肿瘤中，它们在αPD-1和/或αCTLA-4治疗后被重新激活，并显示出一些重叠但主要是治疗特异性的转录谱，使它们能够介导肿瘤排斥反应。这些结果表明，肿瘤特异性突变抗原（TSMA）不仅是检查点阻断治疗的重要靶点，而且可用于开发个性化的癌症特异性疫苗，并探索不同检查点阻断治疗的机制基础。
The immune system plays key roles in determining the fate of developing cancers by not only functioning as a tumour promoter facilitating cellular transformation, promoting tumour growth and sculpting tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer induced immunosuppression. In many individuals, immunosuppression is mediated by Cytotoxic T-Lymphocyte Associated Antigen-4 (CTLA-4) and Programmed Death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal antibody (mAb) based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Herein, we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 therapy of mice bearing progressively growing sarcomas and show that therapeutic synthetic long peptide (SLP) vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Whereas, mutant tumour antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with αPD-1- and/or αCTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens (TSMA) are not only important targets of checkpoint blockade therapy but also can be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.
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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：
10.1
作者：
Fritsch EF;Rajasagi M;Ott PA;Brusic V;Hacohen N;Wu CJ
通讯作者：
Wu CJ
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
影响因子：
9.9
作者：
Lange, Vinzenz;Picotti, Paola;Domon, Bruno;Aebersold, Ruedi
通讯作者：
Aebersold, Ruedi
影响因子：
64.8
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.