PMID- 35339648
OWN - NLM
STAT- MEDLINE
DCOM- 20220620
LR  - 20231104
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Print)
IS  - 0923-7534 (Linking)
VI  - 33
IP  - 7
DP  - 2022 Jul
TI  - HLA class II immunogenic mutation burden predicts response to immune checkpoint 
      blockade.
PG  - 728-738
LID - S0923-7534(22)00392-1 [pii]
LID - 10.1016/j.annonc.2022.03.013 [doi]
AB  - BACKGROUND: Whereas human leukocyte antigen (HLA) class I mutation-associated 
      neoantigen burden has been linked with response to immune checkpoint blockade 
      (ICB), the role of HLA class II-restricted neoantigens in clinical responses to 
      ICB is less studied. We used computational approaches to assess HLA class II 
      immunogenic mutation (IMM) burden in patients with melanoma and lung cancer 
      treated with ICB. PATIENTS AND METHODS: We analyzed whole-exome sequence data 
      from four cohorts of ICB-treated patients with melanoma (n = 110) and 
      non-small-cell lung cancer (NSCLC) (n = 123). MHCnuggets, a neural network-based 
      model, was applied to estimate HLA class II IMM burdens and cellular fractions of 
      IMMs were calculated to assess mutation clonality. We evaluated the combined 
      impact of HLA class II germline genetic variation and class II IMM burden on 
      clinical outcomes. Correlations between HLA class II IMM burden and density of 
      tumor-infiltrating lymphocytes were computed from expression data. RESULTS: 
      Responding tumors harbored a significantly higher HLA class II IMM burden for 
      both melanoma and NSCLC (P </= 9.6e-3). HLA class II IMM burden was correlated with 
      longer survival, particularly in the NSCLC cohort and in the context of low 
      intratumoral IMM heterogeneity (P < 0.001). HLA class I and II IMM landscapes 
      were largely distinct suggesting a complementary role for class II IMMs in tumor 
      rejection. A higher HLA class II IMM burden was associated with CD4+ T-cell 
      infiltration and programmed death-ligand 1 expression. Transcriptomic analyses 
      revealed an inflamed tumor microenvironment for tumors harboring a high HLA class 
      II IMM burden. CONCLUSIONS: HLA class II IMM burden identified patients with 
      NSCLC and melanoma that attained longer survival after ICB treatment. Our 
      findings suggest that HLA class II IMMs may impact responses to ICB in a manner 
      that is distinct and complementary to HLA class I-mediated responses.
CI  - Copyright (c) 2022 European Society for Medical Oncology. Published by Elsevier 
      Ltd. All rights reserved.
FAU - Shao, X M
AU  - Shao XM
AD  - Institute for Computational Medicine, Johns Hopkins University, Baltimore, USA; 
      Department of Biomedical Engineering, Johns Hopkins University, Baltimore, USA.
FAU - Huang, J
AU  - Huang J
AD  - Institute for Computational Medicine, Johns Hopkins University, Baltimore, USA.
FAU - Niknafs, N
AU  - Niknafs N
AD  - The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, USA.
FAU - Balan, A
AU  - Balan A
AD  - The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, USA.
FAU - Cherry, C
AU  - Cherry C
AD  - The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, USA.
FAU - White, J
AU  - White J
AD  - The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, USA.
FAU - Velculescu, V E
AU  - Velculescu VE
AD  - Institute for Computational Medicine, Johns Hopkins University, Baltimore, USA; 
      The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, USA.
FAU - Anagnostou, V
AU  - Anagnostou V
AD  - The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, USA. Electronic address: vanagno1@jhmi.edu.
FAU - Karchin, R
AU  - Karchin R
AD  - Institute for Computational Medicine, Johns Hopkins University, Baltimore, USA; 
      Department of Biomedical Engineering, Johns Hopkins University, Baltimore, USA; 
      The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, USA. Electronic address: karchin@jhu.edu.
LA  - eng
GR  - R01 CA121113/CA/NCI NIH HHS/United States
GR  - UG1 CA233259/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220323
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (HLA Antigens)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Immune Checkpoint Inhibitors)
SB  - IM
EIN - Ann Oncol. 2023 Jul;34(7):634. PMID: 37121856
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology
MH  - HLA Antigens
MH  - Histocompatibility Antigens Class I/genetics
MH  - Humans
MH  - Immune Checkpoint Inhibitors
MH  - *Lung Neoplasms/drug therapy/genetics/pathology
MH  - *Melanoma/drug therapy/genetics/pathology
MH  - Mutation
MH  - Tumor Microenvironment
PMC - PMC10621650
MID - NIHMS1829439
OTO - NOTNLM
OT  - HLA class II neoantigens
OT  - clinical outcome
OT  - immune checkpoint blockade
OT  - immunogenic mutations
COIS- Disclosure Under a license agreement between Genentech and the Johns Hopkins 
      University, XMS and RK and the University are entitled to royalty distributions 
      related to technology described in the study discussed in this publication. This 
      arrangement has been reviewed and approved by the Johns Hopkins University in 
      accordance with its conflict of interest policies. VA receives research funding 
      to her institution from AstraZeneca and has received research funding to her 
      institution from Bristol Myers Squibb in the past 5 years. VEV is a founder of 
      Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of 
      Directors and as a consultant for both organizations, and owns Delfi Diagnostics 
      and Personal Genome Diagnostics stock, which are subject to certain restrictions 
      under university policy. Additionally, Johns Hopkins University owns equity in 
      Delfi Diagnostics and Personal Genome Diagnostics. VEV is an advisor to Bristol 
      Myers Squibb, Genentech, Merck, and Takeda Pharmaceuticals. Within the last 5 
      years, VEV has been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta 
      (these arrangements have been reviewed and approved by the Johns Hopkins 
      University in accordance with its conflict of interest policies). JRW is founder 
      and owner of Resphera Biosciences LLC, and serves as a consultant to Personal 
      Genome Diagnostics Inc. All other authors have declared no conflicts of interest. 
      Ethical approval Regulatory and ethical considerations are described in detail in 
      the original publications from which published data were retrieved to perform the 
      analyses described in this study.
EDAT- 2022/03/28 06:00
MHDA- 2022/06/22 06:00
PMCR- 2023/11/02
CRDT- 2022/03/27 20:21
PHST- 2021/06/23 00:00 [received]
PHST- 2022/03/10 00:00 [revised]
PHST- 2022/03/11 00:00 [accepted]
PHST- 2022/03/28 06:00 [pubmed]
PHST- 2022/06/22 06:00 [medline]
PHST- 2022/03/27 20:21 [entrez]
PHST- 2023/11/02 00:00 [pmc-release]
AID - S0923-7534(22)00392-1 [pii]
AID - 10.1016/j.annonc.2022.03.013 [doi]
PST - ppublish
SO  - Ann Oncol. 2022 Jul;33(7):728-738. doi: 10.1016/j.annonc.2022.03.013. Epub 2022 
      Mar 23.