Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, People's Republic of China.
Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, Suite D-401, Xishan District, Wuxi City, Jiangsu, 214104, People's Republic of China.
Genome Med. 2021 Nov 3;13(1):175. doi: 10.1186/s13073-021-00997-6.
The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive.
This study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts.
Our data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype.
Our results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.
人类白细胞抗原 I 类（HLA-I）基因型与传染病和癌症的免疫反应差异有关。然而，种系 HLA 介导的免疫在胃肠道（GI）癌症中的临床相关性仍不清楚。
本研究回顾性分析了 84 名接受免疫检查点阻断（ICB）治疗的转移性 GI 癌症患者的基因组分析数据，这些患者来自北京大学肿瘤医院（PUCH）。使用 Memorial Sloan Kettering（MSK）癌症中心（MSK GI 队列）的公开数据集作为验证队列。对于 PUCH 队列，我们对所有患者的外周血样本进行了全外显子组测序（WES）分析以进行 HLA 基因分型。对 76 名患者的肿瘤组织进行了 WES 分析和免疫肿瘤学相关的 RNA 分析。我们研究了种系 HLA 的两个参数，即杂合性和进化分歧（HED，衡量 HLA-I 进化的可量化指标）与两个队列中患者的临床结局之间的关联。
我们的数据表明，HLA-A/HLA-C 位点的 HLA 杂合性或 HED 均与 PUCH 队列的总生存期（OS）无关。有趣的是，在 PUCH 和 MSK GI 队列中，HLA-B HED 较高的患者的 OS 优于 HLA-B HED 较低的亚组。值得注意的是，HLA-B HED 和肿瘤突变负荷（TMB）的组合生物标志物可能更好地分层潜在的应答者。此外，HLA-B HED 较高的患者具有多种驱动基因突变的发生率降低和免疫炎症表型的特征。
我们的研究结果揭示了 HLA-B 进化分歧如何影响 GI 癌症患者的 ICB 反应，支持其作为与 TMB 一起用于未来患者分层的组合生物标志物的潜在用途。
