7MJA

HLA-A*24:02 bound to Neuroblastoma derived PHOX2B peptide

7MJA の概要

• エントリーDOI: 10.2210/pdb7mja/pdb
• 分子名称: HLA class I histocompatibility antigen, Beta-2-microglobulin, Paired mesoderm homeobox protein 2B peptide, ... (5 entities in total)
• 機能のキーワード: neuroblastoma tumor antigen, phox2b, igfbpl1, human major histocompatibility complex class i, mhc-i, complex, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 45578.59

構造登録者

Toor, J.S.,Tripathi, S.M.,Truong, H.V.,Yarmarkovich, M.,Maris, J.M.,Sgourakis, N.G. (登録日: 2021-04-19, 公開日: 2021-08-18, 最終更新日: 2024-10-23)

主引用文献

Yarmarkovich, M.,Marshall, Q.F.,Warrington, J.M.,Premaratne, R.,Farrel, A.,Groff, D.,Li, W.,di Marco, M.,Runbeck, E.,Truong, H.,Toor, J.S.,Tripathi, S.,Nguyen, S.,Shen, H.,Noel, T.,Church, N.L.,Weiner, A.,Kendsersky, N.,Martinez, D.,Weisberg, R.,Christie, M.,Eisenlohr, L.,Bosse, K.R.,Dimitrov, D.S.,Stevanovic, S.,Sgourakis, N.G.,Kiefel, B.R.,Maris, J.M.
Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs.
Nature, 599:477-484, 2021

PubMed Abstract: The majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes. However, most cancers have a modest mutational burden that is insufficient to generate responses using neoantigen-based therapies. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins that are essential for tumourigenesis and focus on targeting the unmutated peptide QYNPIRTTF, discovered on HLA-A*24:02, which is derived from the neuroblastoma dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (CARs) using a counter-panning strategy with predicted potentially cross-reactive peptides. We further hypothesized that peptide-centric CARs could recognize peptides on additional HLA allotypes when presented in a similar manner. Informed by computational modelling, we showed that PHOX2B peptide-centric CARs also recognize QYNPIRTTF presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we demonstrated potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.

PubMed: 34732890
DOI: 10.1038/s41586-021-04061-6

実験手法

X-RAY DIFFRACTION (1.69 Å)