Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.
Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.
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DOI：
10.1038/s41591-022-01786-3
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发表时间：
2022-05
期刊：
影响因子：
82.9
通讯作者：
Klebanoff, Christopher A.
中科院分区：
文献类型：
--
作者：
Chandran, Smita S.;Ma, Jiaqi;Klatt, Martin G.;Dundar, Friederike;Bandlamudi, Chaitanya;Razavi, Pedram;Wen, Hannah Y.;Weigelt, Britta;Zumbo, Paul;Fu, Si Ning;Banks, Lauren B.;Yi, Fei;Vercher, Enric;Etxeberria, Inaki;Bestman, Watchain D.;Da Cruz Paula, Arnaud;Aricescu, Ilinca S.;Drilon, Alexander;Betel, Doron;Scheinberg, David A.;Baker, Brian M.;Klebanoff, Christopher A.
公共新抗原（NeoAgs）代表源自反复突变的驱动基因的共享癌症特异性表位的精英类别。在这里，我们描述了一个高通量平台，结合单细胞转录组和T细胞受体（TCR）测序，以确定突变PIK3CA，其中最常见的基因组改变的驱动癌基因，产生免疫原性的公共NeoAg。使用这种策略，我们开发了一组TCR，它们识别一种内源性加工的新肽，其中包含受普遍人类白细胞抗原（HLA）-A * 03：01等位基因限制的常见PIK 3CA热点突变。从机制上讲，对这种公共NeoAg的免疫原性来自于由优选的HLA锚取代引起的增强的新肽/HLA复合物稳定性。结构研究表明，HLA结合的新肽呈现出由肽的骨架主导的相对"无特征"的表面。为了以高特异性和亲和力结合该表位，我们发现前导TCR临床候选物通过由异常长的CDR 3 β环促进的延伸界面接合新肽。在患有不同恶性肿瘤的患者中，我们观察到NeoAg克隆保守性和对新表位的自发免疫原性。最后，TCR工程化T细胞的过继转移导致携带PIK3CA突变型肿瘤但不携带野生型PIK3CA肿瘤的小鼠体内肿瘤消退。总之，这些发现确立了突变体PIK3CA衍生的公共NeoAg的免疫原性和治疗潜力。一个新的高通量平台，以寻找罕见的T细胞，可以识别共享的癌症新抗原鉴定T细胞受体特异性的保守，免疫原性和治疗上可操作的表位突变体PI3K α，最常见的驱动癌基因之一
Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively ‘featureless’ surface dominated by the peptide’s backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg. A new high-throughput platform to find rare T cells that can recognize shared cancer neoantigens identifies T cell receptors specific for a conserved, immunogenic and therapeutically actionable epitope in mutant PI3Kα, one of the most common driver oncogenes
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通过淋巴结消除来清除稳态细胞因子下沉，增强了采用转移的肿瘤特异性CD8+ T细胞的功效。
影响因子：
15.3
作者：
Gattinoni, Luca;Finkelstein, Steven E;Klebanoff, Christopher A;Antony, Paul A;Palmer, Douglas C;Spiess, Paul J;Hwang, Leroy N;Yu, Zhiya;Wrzesinski, Claudia;Heimann, David M;Surh, Charles D;Rosenberg, Steven A;Restifo, Nicholas P
通讯作者：
Restifo, Nicholas P
在肿瘤浸润淋巴细胞上表达的孤儿T细胞受体的抗原鉴定。
影响因子：
64.5
作者：
Gee MH;Han A;Lofgren SM;Beausang JF;Mendoza JL;Birnbaum ME;Bethune MT;Fischer S;Yang X;Gomez-Eerland R;Bingham DB;Sibener LV;Fernandes RA;Velasco A;Baltimore D;Schumacher TN;Khatri P;Quake SR;Davis MM;Garcia KC
通讯作者：
Garcia KC
影响因子：
28.2
作者：
D'Angelo SP;Melchiori L;Merchant MS;Bernstein D;Glod J;Kaplan R;Grupp S;Tap WD;Chagin K;Binder GK;Basu S;Lowther DE;Wang R;Bath N;Tipping A;Betts G;Ramachandran I;Navenot JM;Zhang H;Wells DK;Van Winkle E;Kari G;Trivedi T;Holdich T;Pandite L;Amado R;Mackall CL
通讯作者：
Mackall CL
DOI：
10.1093/jamia/ocw020
发表时间：
2016-07-01
影响因子：
6.4
作者：
Eubank, Michael H.;Hyman, David M.;Stetson, Peter D.
通讯作者：
Stetson, Peter D.
影响因子：
14.8
作者：
Ali, Muhammad;Foldvari, Zsofia;Olweus, Johanna
通讯作者：
Olweus, Johanna