PMID- 34732240
OWN - NLM
STAT- MEDLINE
DCOM- 20220221
LR  - 20240404
IS  - 1756-994X (Electronic)
IS  - 1756-994X (Linking)
VI  - 13
IP  - 1
DP  - 2021 Nov 3
TI  - Germline HLA-B evolutionary divergence influences the efficacy of immune 
      checkpoint blockade therapy in gastrointestinal cancer.
PG  - 175
LID - 10.1186/s13073-021-00997-6 [doi]
LID - 175
AB  - 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.
CI  - (c) 2021. The Author(s).
FAU - Lu, Zhihao
AU  - Lu Z
AD  - 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.
FAU - Chen, Huan
AU  - Chen H
AD  - Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, 
      Suite D-401, Xishan District, Wuxi City, Jiangsu, 214104, People's Republic of 
      China.
FAU - Jiao, Xi
AU  - Jiao X
AD  - 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.
FAU - Wang, Yujiao
AU  - Wang Y
AD  - 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.
FAU - Wu, Lijia
AU  - Wu L
AD  - Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, 
      Suite D-401, Xishan District, Wuxi City, Jiangsu, 214104, People's Republic of 
      China.
FAU - Sun, Huaibo
AU  - Sun H
AD  - Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, 
      Suite D-401, Xishan District, Wuxi City, Jiangsu, 214104, People's Republic of 
      China.
FAU - Li, Shuang
AU  - Li S
AD  - 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.
FAU - Gong, Jifang
AU  - Gong J
AD  - 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.
FAU - Li, Jian
AU  - Li J
AD  - 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.
FAU - Zou, Jianling
AU  - Zou J
AD  - 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.
FAU - Yang, Keyan
AU  - Yang K
AD  - Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, 
      Suite D-401, Xishan District, Wuxi City, Jiangsu, 214104, People's Republic of 
      China.
FAU - Hu, Ying
AU  - Hu Y
AD  - Biomedical Innovation Center, Beijing Shijitan Hospital, School of Oncology, 
      Capital Medical University, Beijing, People's Republic of China.
FAU - Mao, Beibei
AU  - Mao B
AD  - Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, 
      Suite D-401, Xishan District, Wuxi City, Jiangsu, 214104, People's Republic of 
      China.
FAU - Zhang, Lei
AU  - Zhang L
AD  - Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, 
      Suite D-401, Xishan District, Wuxi City, Jiangsu, 214104, People's Republic of 
      China.
FAU - Zhang, Xiaotian
AU  - Zhang X
AD  - 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.
FAU - Peng, Zhi
AU  - Peng Z
AD  - 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.
FAU - Lu, Ming
AU  - Lu M
AD  - 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.
FAU - Wang, Zhenghang
AU  - Wang Z
AD  - 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.
FAU - Zhang, Henghui
AU  - Zhang H
AD  - Biomedical Innovation Center, Beijing Shijitan Hospital, School of Oncology, 
      Capital Medical University, Beijing, People's Republic of China. 
      zhhbao@ccmu.edu.cn.
FAU - Shen, Lin
AU  - Shen L
AD  - 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. shenlin@bjmu.edu.cn.
LA  - eng
SI  - figshare/10.6084/m9.figshare.16607891
SI  - figshare/10.6084/m9.figshare.16607894
SI  - figshare/10.6084/m9.figshare.16607900
SI  - figshare/10.6084/m9.figshare.14179295
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211103
PL  - England
TA  - Genome Med
JT  - Genome medicine
JID - 101475844
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (HLA-B Antigens)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Immune Checkpoint Inhibitors)
SB  - IM
MH  - Biomarkers, Tumor/genetics
MH  - Cohort Studies
MH  - Gastrointestinal Neoplasms/*genetics/*therapy
MH  - Genotype
MH  - *Germ Cells
MH  - HLA-B Antigens/*genetics
MH  - Histocompatibility Antigens Class I/genetics
MH  - Humans
MH  - Immune Checkpoint Inhibitors/*therapeutic use
MH  - Immunotherapy/*methods
MH  - Mutation
MH  - Retrospective Studies
PMC - PMC8567649
OTO - NOTNLM
OT  - Gastrointestinal cancer
OT  - HLA genotype
OT  - HLA-I evolutionary divergence
OT  - Immune checkpoint blockade
OT  - Tumor mutational burden
COIS- The authors declare that they have no competing interests.
EDAT- 2021/11/05 06:00
MHDA- 2022/02/22 06:00
PMCR- 2021/11/03
CRDT- 2021/11/04 05:30
PHST- 2021/03/08 00:00 [received]
PHST- 2021/10/22 00:00 [accepted]
PHST- 2021/11/04 05:30 [entrez]
PHST- 2021/11/05 06:00 [pubmed]
PHST- 2022/02/22 06:00 [medline]
PHST- 2021/11/03 00:00 [pmc-release]
AID - 10.1186/s13073-021-00997-6 [pii]
AID - 997 [pii]
AID - 10.1186/s13073-021-00997-6 [doi]
PST - epublish
SO  - Genome Med. 2021 Nov 3;13(1):175. doi: 10.1186/s13073-021-00997-6.