Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Cologne, Germany.
J Immunother Cancer. 2024 Apr 17;12(4):e007268. doi: 10.1136/jitc-2023-007268.
The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides.
HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses.
We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele.
The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.
个体 HLA-I 基因型与癌症、自身免疫性疾病和感染有关。本研究阐明了 HLA-I 基因座的种系纯合性或等位基因失衡在食管胃腺癌（EGA）中的作用，并确定了潜在免疫原性肽的反应谱。
使用（1）10 种相关肿瘤相关抗原（TAA）或（2）患者特异性突变相关新抗原（MAA）的 HLA 基因型和序列，通过 MHC 结合的计算方法（www.iedb.org）预测良好亲和力结合物。通过转录组测序分析 HLA-I-A/B/C 等位基因的不平衡或缺失表达。使用 FluoroSpot 测定和 TCR 测序来确定肽特异性 T 细胞反应。
我们表明，与 HLA 匹配的参考队列（n=7605）相比，HLA-I 基因的种系纯合性在 EGA 患者（n=80）中显著富集。虽然总体突变负担相似，但源自 TAA 和 MAA 的潜在免疫原性肽的反应谱在纯合患者中较低。大多数 TAA 和 MAA 的肽与不同 HLA-I 分子结合的混杂性较低，并且对纯合至杂合 HLA 基因型的计算建模揭示了正常的肽反应谱。转录组测序显示，75%的杂合患者中 HLA-I 等位基因表达失衡。其中，33%表现出完全的杂合性丢失，而 66%仅有一个或两个 HLA-I 分子的表达改变。在 FluoroSpot 测定中，我们确定针对 NY-ESO-1 的肽特异性 T 细胞反应来自多个肽，这些肽通常仅特异性结合一个 HLA-I 等位基因。
EGA 患者中 HLA-I 基因型的种系纯合性频率较高表明癌症免疫监视减少，导致癌症风险增加。在 EGA 中应考虑针对 HLA-I 分子的等位基因失衡的治疗靶向。
Zotero 插件
