George Mariam M, Brennick Cory A, Hagymasi Adam T, Shcheglova Tatiana V, Al Seesi Sahar, Rosales Tatiana J, Baker Brian M, Mandoiu Ion I, Srivastava Pramod K
Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, United States.
Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, United States.
J Immunol. 2025 Jun 1;214(6):1123-1132. doi: 10.1093/jimmun/vkaf016.
Insertion or deletion of one or two base pairs within a coding region causes a frameshift, which has the potential to generate neoepitopes (InDel-generated neoepitopes) that lack a self-counterpart and are entirely novel. Despite the obvious appeal of InDel-generated neoepitopes, and the demonstration of such candidate neoepitopes that can elicit a CD8 T-cell response, no InDel-generated neoepitopes that actually control tumors in vivo have been reported thus far. Here, in a mouse colon carcinoma line, we identify 11 InDels, only one of which generates a neoepitope that elicits tumor control in vivo in models of prophylaxis as well as therapy. Although this neoepitope has no self-counterpart, it has a low affinity (IC50 33,937.60 nM) for its MHC I allele. Despite its low affinity for MHC I, this neoepitope elicits antitumor activity in vivo through CD8 T cells. Furthermore, CD8 T cells elicited by this InDel-generated neoepitope, like the neoepitopes created by point mutations, show notably less exhaustion than classical immunogenic epitopes. Ironically, this InDel-generated neoepitope follows the same rules as noted for most of the tumor control-mediating neoepitopes generated by point mutations that have a poor affinity for MHC I alleles.
编码区内一个或两个碱基对的插入或缺失会导致移码突变，这有可能产生缺乏自身对应物且全新的新抗原（InDel产生的新抗原）。尽管InDel产生的新抗原具有明显的吸引力，并且已经证明了此类候选新抗原能够引发CD8 T细胞反应，但迄今为止，尚未有关于在体内实际控制肿瘤的InDel产生的新抗原的报道。在此，我们在一种小鼠结肠癌细胞系中鉴定出11个插入缺失（InDel），其中只有一个产生的新抗原在预防和治疗模型中能在体内引发肿瘤控制。尽管这个新抗原没有自身对应物，但其对MHC I等位基因的亲和力较低（IC50为33,937.60 nM）。尽管它对MHC I的亲和力较低，但这个新抗原通过CD8 T细胞在体内引发抗肿瘤活性。此外，由这个InDel产生的新抗原引发的CD8 T细胞，与点突变产生的新抗原一样，与经典免疫原性表位相比，耗竭程度明显更低。具有讽刺意味的是，这个InDel产生的新抗原遵循的规则与大多数对MHC I等位基因亲和力较差的点突变产生的介导肿瘤控制的新抗原相同。
