Shinkawa Tomoyo, Tokita Serina, Nakatsugawa Munehide, Kikuchi Yasuhiro, Kanaseki Takayuki, Torigoe Toshihiko
Department of Pathology, Sapporo Medical University, Sapporo, Japan.
Academic center, Sapporo Dohto Hospital, Sapporo, Japan.
Oncoimmunology. 2021 Jan 18;10(1):1870062. doi: 10.1080/2162402X.2020.1870062.
CD8 T cells are capable of recognizing mutation-derived neoantigens displayed by HLA class I molecules, thereby exhibiting the ability to distinguish between cancer and normal cells. However, accumulating evidence has shown that only a small fraction of nonsynonymous somatic mutations give rise to clinically relevant neoantigens. The properties of such neoantigens, which must be presented by HLA and immunogenic to induce a T-cell response, remain elusive. In this study, we explored the HLA class I ligandome of a human cancer cell line with microsatellite instability using a proteogenomic approach. The results demonstrated that neoantigens accounted for only 0.34% of the HLA class I ligandome, and most neoantigens were encoded by genes with abundant expression. Thereafter, T-cell responses were prioritized, and immunodominant neoantigens were defined using naive CD8 T cells derived from healthy donors. AKF9, an immunogenic neoantigen with a mutation at a non-anchor position, formed a stable peptide-HLA complex. T-cell responses were analyzed against a panel of AKF9 variants with single amino-acid substitutions, in which mutations did not alter the high HLA-binding affinity and stability. The responses varied across individuals, demonstrating the impact of heterogeneous T-cell repertoires in this human cancer model. Moreover, responses were biased toward a variant group with large structural changes compared to the wild-type peptide. Thus, naive T-cell induction can be attributed to multiple determinants. Combining structural dissimilarity with gene-expression levels, HLA-binding affinity, and stability may further help prioritize the immunogenicity of non-anchor-type neoantigens.
CD8 T细胞能够识别由HLA I类分子呈递的源自突变的新抗原，从而展现出区分癌细胞和正常细胞的能力。然而，越来越多的证据表明，只有一小部分非同义体细胞突变会产生具有临床相关性的新抗原。这类新抗原的特性仍不清楚，它们必须由HLA呈递且具有免疫原性才能诱导T细胞反应。在本研究中，我们使用蛋白质基因组学方法探索了具有微卫星不稳定性的人类癌细胞系的HLA I类配体组。结果表明，新抗原仅占HLA I类配体组的0.34%，且大多数新抗原由高表达基因编码。此后，我们对T细胞反应进行了优先级排序，并使用来自健康供体的初始CD8 T细胞定义了免疫显性新抗原。AKF9是一种在非锚定位置发生突变的免疫原性新抗原，它形成了稳定的肽-HLA复合物。我们分析了针对一组具有单氨基酸替换的AKF9变体的T细胞反应，其中这些突变并未改变高HLA结合亲和力和稳定性。不同个体的反应各不相同，这表明在这个人类癌症模型中T细胞库的异质性产生了影响。此外，与野生型肽相比，反应偏向于具有较大结构变化的变体组。因此，初始T细胞诱导可归因于多种决定因素。将结构差异与基因表达水平、HLA结合亲和力和稳定性相结合，可能进一步有助于确定非锚定型新抗原的免疫原性优先级。
