Ionizing Radiation Drives Key Regulators of Antigen Presentation and a Global Expansion of the Immunopeptidome.
Ionizing Radiation Drives Key Regulators of Antigen Presentation and a Global Expansion of the Immunopeptidome.
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DOI：
10.1016/j.mcpro.2022.100410
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发表时间：
2022-11
影响因子：
7
通讯作者：
Ternette, Nicola
中科院分区：
文献类型：
--
作者：
Tailor, Arun;Estephan, Hala;Parker, Robert;Woodhouse, Isaac;Abdulghani, Majd;Nicastri, Annalisa;Jones, Keaton;Salatino, Silvia;Muschel, Ruth;Humphrey, Timothy;Giaccia, Amato;Ternette, Nicola
人们对调节 MHC 抗原呈递的途径以及电离辐射诱导的治疗特异性 T 细胞抗原的身份知之甚少。为此，我们研究了结直肠肿瘤细胞蛋白质组的辐射特异性变化。我们发现 DDX58 和 ZBP1 蛋白表达增加，这两种核酸传感分子可能参与诱导基因毒性损伤后观察到的主要干扰素反应特征。我们进一步观察了治疗引起的抗原加工和呈递机制的关键调节因子和效应蛋白的变化。 MHC 等位基因表达的差异调节进一步推动了辐射后显着更广泛的 MHC 相关肽组的呈现，定义了辐射特异性肽库。有趣的是，治疗诱导的肽主要源自参与儿茶酚胺合成和代谢途径的蛋白质。观察到蛋白质表达和抗原呈递之间的微妙关系，其中辐射诱导的蛋白质变化与相关肽呈递的增加不相关。最后，我们检测到源自 Mtch1 的肿瘤特异性新抗原的表达增加。这项研究提供了关于辐射如何增强抗原加工和呈递的新见解，这可能适合组合疗法的开发。数据可通过 ProteomeXchange 获得，标识符为 PXD032003。 CT26 和 MC38 中的抗原呈递途径是由辐射诱导的。辐射诱导的扩增免疫肽组含有辐射特异性肽。辐射特异性效应以时间依赖性方式增加。 CT26 的外显子组测序揭示了一种可由辐射诱导的新抗原。众所周知，使用放射疗法的癌症治疗会激活免疫系统。在这里，我们发现辐射增加了免疫系统的信号成分，称为肿瘤细胞上的主要组织相容性复合体。这种增加使得肿瘤更容易被 T 细胞识别，T 细胞的作用是特异性发现并杀死有缺陷或突变的细胞。这些发现可以为医生提供将放射治疗与免疫疗法结合起来的理由，以利用放射的免疫效应来获得治疗效果。
Little is known about the pathways regulating MHC antigen presentation and the identity of treatment-specific T cell antigens induced by ionizing radiation. For this reason, we investigated the radiation-specific changes in the colorectal tumor cell proteome. We found an increase in DDX58 and ZBP1 protein expression, two nucleic acid sensing molecules likely involved in induction of the dominant interferon response signature observed after genotoxic insult. We further observed treatment-induced changes in key regulators and effector proteins of the antigen processing and presentation machinery. Differential regulation of MHC allele expression was further driving the presentation of a significantly broader MHC-associated peptidome postirradiation, defining a radiation-specific peptide repertoire. Interestingly, treatment-induced peptides originated predominantly from proteins involved in catecholamine synthesis and metabolic pathways. A nuanced relationship between protein expression and antigen presentation was observed where radiation-induced changes in proteins do not correlate with increased presentation of associated peptides. Finally, we detected an increase in the presentation of a tumor-specific neoantigen derived from Mtch1. This study provides new insights into how radiation enhances antigen processing and presentation that could be suitable for the development of combinatorial therapies. Data are available via ProteomeXchange with identifier PXD032003. The antigen presentation pathway is induced by radiation in CT26 and MC38. A radiation-induced expanded immunopeptidome contains radiation-specific peptides. Radiation-specific effects increase in a time-dependent manner. Exome sequencing of CT26 reveals a neoantigen which can be induced by radiation. It has been known that cancer treatment using radiation therapy activates the immune system. Here, we show that radiation increases a signaling component of the immune system called the major histocompatibility complex on tumor cells. This increase makes the tumor more recognizable to T cells whose roles are to specifically find and kill defective or mutated cells. These findings could give physicians a reason to combine radiation therapy with immunotherapies to use the immune effect of radiation for therapeutic benefits.
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影响因子：
3.6
作者：
Jongsma, Marlieke L. M.;Guarda, Greta;Spaapen, Robbert M.
通讯作者：
Spaapen, Robbert M.
影响因子：
82.9
作者：
Formenti SC;Rudqvist NP;Golden E;Cooper B;Wennerberg E;Lhuillier C;Vanpouille-Box C;Friedman K;Ferrari de Andrade L;Wucherpfennig KW;Heguy A;Imai N;Gnjatic S;Emerson RO;Zhou XK;Zhang T;Chachoua A;Demaria S
通讯作者：
Demaria S
影响因子：
--
作者：
Garcia, Maxime;Juhos, Szilveszter;Nystedt, Bjorn
通讯作者：
Nystedt, Bjorn
影响因子：
4.4
作者：
Castle JC;Loewer M;Boegel S;de Graaf J;Bender C;Tadmor AD;Boisguerin V;Bukur T;Sorn P;Paret C;Diken M;Kreiter S;Türeci Ö;Sahin U
通讯作者：
Sahin U
影响因子：
15.9
作者：
Chen, Jianzhou;Cao, Yunhong;Muschel, Ruth J.
通讯作者：
Muschel, Ruth J.