化学蛋白质组学揭示了源自肿瘤酶CK2α的免疫原性和肿瘤相关的细胞表面底物
Chemoproteomics reveals immunogenic and tumor-associated cell surface substrates of ectokinase CK2α
影响因子:7.20000
分区:生物学1区 Top / 生化与分子生物学2区
发表日期:2024 Sep 19
作者:
Corleone S Delaveris, Sophie Kong, Jeff Glasgow, Rita P Loudermilk, Lisa L Kirkemo, Fangzhu Zhao, Fernando Salangsang, Paul Phojanakong, Juan Antonio Camara Serrano, Veronica Steri, James A Wells
摘要
外国免疫识别的表位提供了抗癌免疫的基础。由于肿瘤微环境中三磷酸的细胞外腺苷浓度高，我们假设细胞外激酶（Ectokinase）可能具有失调的活性，并在细胞表面蛋白上引入异常的磷酸化位点。我们设计了细胞外激酶CK2α的细胞螺旋形式，证明它在肿瘤相关条件下活跃在细胞上，并使用化学蛋白质组学工作流进行了底物范围。然后，我们证明了小鼠在响应于与CK2α进行表面过度磷酸化的合成性肿瘤细胞的响应后形成了多反应性抗血清。有趣的是，这些小鼠对这些抗原产生了B细胞和CD4+ T细胞反应，但未能产生CD8+ T细胞反应。这项工作提供了探测细胞外磷酸蛋白质组的工作流程，并证明即使在合成系统中，细胞外磷蛋白也是免疫原性的。
Abstract
Foreign epitopes for immune recognition provide the basis of anticancer immunity. Due to the high concentration of extracellular adenosine triphosphate in the tumor microenvironment, we hypothesized that extracellular kinases (ectokinases) could have dysregulated activity and introduce aberrant phosphorylation sites on cell surface proteins. We engineered a cell-tethered version of the extracellular kinase CK2α, demonstrated it was active on cells under tumor-relevant conditions, and profiled its substrate scope using a chemoproteomic workflow. We then demonstrated that mice developed polyreactive antisera in response to syngeneic tumor cells that had been subjected to surface hyperphosphorylation with CK2α. Interestingly, these mice developed B cell and CD4+ T cell responses in response to these antigens but failed to develop a CD8+ T cell response. This work provides a workflow for probing the extracellular phosphoproteome and demonstrates that extracellular phosphoproteins are immunogenic even in a syngeneic system.