PMID- 32927123
OWN - NLM
STAT- MEDLINE
DCOM- 20210401
LR  - 20220531
IS  - 1556-1380 (Electronic)
IS  - 1556-0864 (Print)
IS  - 1556-0864 (Linking)
VI  - 16
IP  - 1
DP  - 2021 Jan
TI  - HLA Class I Binding of Mutant EGFR Peptides in NSCLC Is Associated With Improved 
      Survival.
PG  - 104-112
LID - S1556-0864(20)30715-2 [pii]
LID - 10.1016/j.jtho.2020.08.023 [doi]
AB  - INTRODUCTION: Cancer-associated mutations have the potential to generate 
      neoantigens and elicit CD8-positive T-cell-dependent adaptive immune responses. 
      There are currently no reports of CD8-positive T-cells with specificity for 
      neoepitopes generated by EGFR mutations, which are driver oncogenes in a subset 
      of patients with lung cancer. METHODS: We used NETMHCpan 4.0 to identify putative 
      protective human leukocyte antigen (HLA) class I allotypes that are predicted in 
      silico to bind and present mutant EGFR-generated peptides on the basis of 
      predefined criteria. We associated the presence or absence of these alleles with 
      clinical outcomes in patients from The Cancer Genome Atlas with lung 
      adenocarcinoma. RESULTS: We identified 12 HLA class I alleles that fulfilled the 
      predefined criteria for being protective for EGFR p.L858R and six for EGFR 
      p.E746_A750del, the two most common EGFR mutations in lung cancer. We validated 
      the in silico predictions for peptide-HLA allele binding in vitro. A third (12 of 
      36) of patients with mostly early stage lung adenocarcinoma in The Cancer Genome 
      Atlas with either EGFR p.L858R or EGFR p.E746_A750del had at least one protective 
      allele in their host genomes. More importantly, patients with protective alleles 
      exhibited better disease-free (hazard ratio: 0.20, 95% confidence interval: 
      0.05-0.78) and overall survival (hazard ratio: 0.13, 95% confidence interval: 
      0.02-0.64), and this effect was independent of the EGFR mutation type, stage, 
      age, and sex. CONCLUSIONS: Our data revealed that clinical outcomes were improved 
      in patients with EGFR mutation-positive lung adenocarcinoma who harbored 
      protective HLA class I alleles. Thus, immunity with specificity for mutant EGFR 
      is possible in a subset of patients with early stage lung cancer and portends a 
      better prognosis.
CI  - Copyright (c) 2020 International Association for the Study of Lung Cancer. 
      Published by Elsevier Inc. All rights reserved.
FAU - Dimou, Anastasios
AU  - Dimou A
AD  - Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, 
      Colorado; Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota. 
      Electronic address: robert.doebele@ucdenver.edu.
FAU - Grewe, Paul
AU  - Grewe P
AD  - Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, 
      Colorado.
FAU - Sidney, John
AU  - Sidney J
AD  - La Jolla Institute for Immunology, La Jolla, California.
FAU - Sette, Alessandro
AU  - Sette A
AD  - La Jolla Institute for Immunology, La Jolla, California; Department of Medicine, 
      University of California in San Diego, La Jolla, California.
FAU - Norman, Paul J
AU  - Norman PJ
AD  - Division of Biomedical Informatics and Personalized Medicine, School of Medicine, 
      University of Colorado, Aurora, Colorado; Department of Microbiology and 
      Immunology, School of Medicine, University of Colorado, Aurora, Colorado.
FAU - Doebele, Robert C
AU  - Doebele RC
AD  - Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, 
      Colorado.
LA  - eng
GR  - U01 AI090905/AI/NIAID NIH HHS/United States
GR  - R21 AI134127/AI/NIAID NIH HHS/United States
GR  - R01 AI128775/AI/NIAID NIH HHS/United States
GR  - P50 CA058187/CA/NCI NIH HHS/United States
GR  - 75N93019C00001/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200911
PL  - United States
TA  - J Thorac Oncol
JT  - Journal of thoracic oncology : official publication of the International 
      Association for the Study of Lung Cancer
JID - 101274235
RN  - 0 (Peptides)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - *Adenocarcinoma of Lung
MH  - *Carcinoma, Non-Small-Cell Lung/genetics
MH  - ErbB Receptors/genetics
MH  - Humans
MH  - *Lung Neoplasms/genetics
MH  - Mutation
MH  - Peptides/genetics
PMC - PMC7797166
MID - NIHMS1629540
OTO - NOTNLM
OT  - Adaptive immunity
OT  - EGFR
OT  - HLA
OT  - Neoepitopes
EDAT- 2020/09/15 06:00
MHDA- 2021/04/02 06:00
PMCR- 2022/01/01
CRDT- 2020/09/14 20:13
PHST- 2019/12/13 00:00 [received]
PHST- 2020/07/11 00:00 [revised]
PHST- 2020/08/30 00:00 [accepted]
PHST- 2020/09/15 06:00 [pubmed]
PHST- 2021/04/02 06:00 [medline]
PHST- 2020/09/14 20:13 [entrez]
PHST- 2022/01/01 00:00 [pmc-release]
AID - S1556-0864(20)30715-2 [pii]
AID - 10.1016/j.jtho.2020.08.023 [doi]
PST - ppublish
SO  - J Thorac Oncol. 2021 Jan;16(1):104-112. doi: 10.1016/j.jtho.2020.08.023. Epub 
      2020 Sep 11.