小柯机器人

美国纪念斯隆-凯特琳癌症中心Christopher A. Klebanoff、Smita S. Chandran等研究人员合作揭示，来自突变的PIK3CA的公共新抗原的免疫原性和治疗靶标。相关论文于2022年4月28日在线发表在《自然—医学》杂志上。

研究人员描述了一个结合单细胞转录组和T细胞受体（TCR）测序的高通量平台，以确定突变的PIK3CA（最频繁的基因组改变的驱动致癌基因之一）是否产生了一个免疫原性的公共新抗原（NeoAg）。利用这一策略，研究人员开发了一个TCR小组，它能识别一个内源性加工的新肽，其中包括一个由流行的人类白细胞抗原（HLA）-A*03:01等位基因限制的普通PIK3CA热点突变。从机制上讲，这种公共NeoAg的免疫原性来自于由优先的HLA锚替代引起的新肽/HLA复合物稳定性的增强。结构研究表明，与HLA结合的新肽呈现一个相对"无特征"的表面，由肽的骨架主导。

为了以高特异性和高亲和力结合这一表位，研究人员发现一个领先的TCR临床候选者通过一个由异常长的CDR3β环促成的扩展接口与新肽结合。在不同的恶性肿瘤患者中，研究人员观察到NeoAg的克隆保存和对新肽的自发免疫原性。最后，TCR工程化的T细胞的过继转移导致了携带PIK3CA突变体肿瘤小鼠体内的肿瘤消退，而不是野生型PIK3CA肿瘤。这些发现共同确立了突变型PIK3CA衍生的公共NeoAg的免疫原性和治疗潜力。

据了解，公共NeoAg代表了来自反复突变的驱动基因的共享癌症特异性表位的一个精英类别。

附：英文原文

Title: Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA

Author: Chandran, Smita S., Ma, Jiaqi, Klatt, Martin G., Dndar, 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.

Issue&Volume: 2022-04-28

Abstract: 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.

DOI: 10.1038/s41591-022-01786-3

Source: https://www.nature.com/articles/s41591-022-01786-3

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex