Reversion analysis reveals the in vivo immunogenicity of a poorly MHC I-binding cancer neoepitope.
Reversion analysis reveals the in vivo immunogenicity of a poorly MHC I-binding cancer neoepitope.
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DOI：
10.1038/s41467-021-26646-5
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发表时间：
2021-11-05
影响因子：
16.6
通讯作者：
Srivastava PK
中科院分区：
文献类型：
--
作者：
Ebrahimi-Nik H;Moussa M;Englander RP;Singhaviranon S;Michaux J;Pak H;Miyadera H;Corwin WL;Keller GLJ;Hagymasi AT;Shcheglova TV;Coukos G;Baker BM;Mandoiu II;Bassani-Sternberg M;Srivastava PK
高亲和力MHC i肽相互作用被认为是免疫原性的必要条件。然而，一些与MHC I低亲和力的新表位在免疫激发研究中引起CD8 T细胞依赖性肿瘤排斥反应。在这里，我们在小鼠模型中表明，在缺乏免疫的情况下，与MHC I结合不良的新表位能够增强肿瘤的免疫原性。具有自然发生突变的纤维肉瘤细胞被编辑成野生型对应物；然后重新引入该突变，以获得除新表位编码突变外与野生型基因相同的细胞系。在移植到同基因小鼠体内后，这三种细胞系都形成了被活化的T细胞浸润的肿瘤。然而，与野生型肿瘤相比，来自两种携带突变的肿瘤的淋巴细胞表现出更强的细胞毒性和TCR参与的转录特征，并诱导更宽的TCR反应性。新表位肽/MHC I对的结构建模表明，新表位表面的疏水性增加，与更高的TCR反应性一致。这些结果证实了低亲和力或“非结合”表位的体内免疫原性，这些表位不遵循MHC i肽识别的规范概念。肽的免疫原性被认为是由它们与MHC i的高亲和力结合决定的。本文作者表明，低亲和力MHC i肽的相互作用也能够在体内触发强大的T细胞反应和抗肿瘤免疫。
High-affinity MHC I-peptide interactions are considered essential for immunogenicity. However, some neo-epitopes with low affinity for MHC I have been reported to elicit CD8 T cell dependent tumor rejection in immunization-challenge studies. Here we show in a mouse model that a neo-epitope that poorly binds to MHC I is able to enhance the immunogenicity of a tumor in the absence of immunization. Fibrosarcoma cells with a naturally occurring mutation are edited to their wild type counterpart; the mutation is then re-introduced in order to obtain a cell line that is genetically identical to the wild type except for the neo-epitope-encoding mutation. Upon transplantation into syngeneic mice, all three cell lines form tumors that are infiltrated with activated T cells. However, lymphocytes from the two tumors that harbor the mutation show significantly stronger transcriptional signatures of cytotoxicity and TCR engagement, and induce greater breadth of TCR reactivity than those of the wild type tumors. Structural modeling of the neo-epitope peptide/MHC I pairs suggests increased hydrophobicity of the neo-epitope surface, consistent with higher TCR reactivity. These results confirm the in vivo immunogenicity of low affinity or ‘non-binding’ epitopes that do not follow the canonical concept of MHC I-peptide recognition. The immunogenicity of peptides is believed to be determined by their high-affinity binding to MHC I. Here authors show that low-affinity MHC I-peptide interactions are also able to trigger robust T cell response and anti-tumour immunity in vivo.
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影响因子：
29.7
作者：
Blum JS;Wearsch PA;Cresswell P
通讯作者：
Cresswell P
影响因子：
11.2
作者：
Castle, John C.;Kreiter, Sebastian;Sahin, Ugur
通讯作者：
Sahin, Ugur
影响因子：
2.2
作者：
Duan, Fei;Simeone, Shauna;Srivastava, Pramod K.
通讯作者：
Srivastava, Pramod K.
影响因子：
10.1
作者：
Rech AJ;Balli D;Mantero A;Ishwaran H;Nathanson KL;Stanger BZ;Vonderheide RH
通讯作者：
Vonderheide RH
DOI：
10.4049/jimmunol.1701523
发表时间：
2018-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Frey BF;Jiang J;Sui Y;Boyd LF;Yu B;Tatsuno G;Billeskov R;Solaymani-Mohammadi S;Berman PW;Margulies DH;Berzofsky JA
通讯作者：
Berzofsky JA