Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

Abstract Background 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. Methods This study retrospe...

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Autores principales:	Zhihao Lu, Huan Chen, Xi Jiao, Yujiao Wang, Lijia Wu, Huaibo Sun, Shuang Li, Jifang Gong, Jian Li, Jianling Zou, Keyan Yang, Ying Hu, Beibei Mao, Lei Zhang, Xiaotian Zhang, Zhi Peng, Ming Lu, Zhenghang Wang, Henghui Zhang, Lin Shen
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Immune checkpoint blockade Gastrointestinal cancer HLA genotype HLA-I evolutionary divergence Tumor mutational burden Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/7fe821b76fe44e51931ca85d2de5d647
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spelling	oai:doaj.org-article:7fe821b76fe44e51931ca85d2de5d6472021-11-08T10:57:57ZGermline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer10.1186/s13073-021-00997-61756-994Xhttps://doaj.org/article/7fe821b76fe44e51931ca85d2de5d6472021-11-01T00:00:00Zhttps://doi.org/10.1186/s13073-021-00997-6https://doaj.org/toc/1756-994XAbstract Background 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. Methods 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. Results 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. Conclusions 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.Zhihao LuHuan ChenXi JiaoYujiao WangLijia WuHuaibo SunShuang LiJifang GongJian LiJianling ZouKeyan YangYing HuBeibei MaoLei ZhangXiaotian ZhangZhi PengMing LuZhenghang WangHenghui ZhangLin ShenBMCarticleImmune checkpoint blockadeGastrointestinal cancerHLA genotypeHLA-I evolutionary divergenceTumor mutational burdenMedicineRGeneticsQH426-470ENGenome Medicine, Vol 13, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immune checkpoint blockade Gastrointestinal cancer HLA genotype HLA-I evolutionary divergence Tumor mutational burden Medicine R Genetics QH426-470
spellingShingle	Immune checkpoint blockade Gastrointestinal cancer HLA genotype HLA-I evolutionary divergence Tumor mutational burden Medicine R Genetics QH426-470 Zhihao Lu Huan Chen Xi Jiao Yujiao Wang Lijia Wu Huaibo Sun Shuang Li Jifang Gong Jian Li Jianling Zou Keyan Yang Ying Hu Beibei Mao Lei Zhang Xiaotian Zhang Zhi Peng Ming Lu Zhenghang Wang Henghui Zhang Lin Shen Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer
description	Abstract Background 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. Methods 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. Results 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. Conclusions 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.
format	article
author	Zhihao Lu Huan Chen Xi Jiao Yujiao Wang Lijia Wu Huaibo Sun Shuang Li Jifang Gong Jian Li Jianling Zou Keyan Yang Ying Hu Beibei Mao Lei Zhang Xiaotian Zhang Zhi Peng Ming Lu Zhenghang Wang Henghui Zhang Lin Shen
author_facet	Zhihao Lu Huan Chen Xi Jiao Yujiao Wang Lijia Wu Huaibo Sun Shuang Li Jifang Gong Jian Li Jianling Zou Keyan Yang Ying Hu Beibei Mao Lei Zhang Xiaotian Zhang Zhi Peng Ming Lu Zhenghang Wang Henghui Zhang Lin Shen
author_sort	Zhihao Lu
title	Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer
title_short	Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer
title_full	Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer
title_fullStr	Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer
title_full_unstemmed	Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer
title_sort	germline hla-b evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer
publisher	BMC
publishDate	2021
url	https://doaj.org/article/7fe821b76fe44e51931ca85d2de5d647
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Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

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