Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, USA.
Broad Institute of MIT and Harvard, 105 Broadway, Cambridge, MA, USA.
Nat Commun. 2021 Nov 5;12(1):6423. doi: 10.1038/s41467-021-26646-5.
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.
高亲和力 MHC I-肽相互作用被认为对免疫原性至关重要。然而，一些低亲和力 MHC I 的新表位已被报道在免疫接种挑战研究中引发 CD8 T 细胞依赖性肿瘤排斥。在这里，我们在小鼠模型中表明，一种与 MHC I 结合能力差的新表位能够在没有免疫接种的情况下增强肿瘤的免疫原性。具有天然发生突变的纤维肉瘤细胞被编辑为其野生型对应物；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完全相同的细胞系。将其移植到同基因小鼠中，所有三种细胞系均形成肿瘤，肿瘤浸润有激活的 T 细胞。然而，携带突变的两种肿瘤的淋巴细胞显示出明显更强的细胞毒性和 TCR 结合的转录特征，并诱导比野生型肿瘤更大的 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，这些表位不符合 MHC I-肽识别的经典概念。
