PMID- 33127846
OWN - NLM
STAT- MEDLINE
DCOM- 20220114
LR  - 20220114
IS  - 2159-8290 (Electronic)
IS  - 2159-8274 (Linking)
VI  - 11
IP  - 2
DP  - 2021 Feb
TI  - Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which 
      Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor 
      Response.
PG  - 282-292
LID - 10.1158/2159-8290.CD-20-0672 [doi]
AB  - Neoantigen presentation arises as a result of tumor-specific mutations and is a 
      critical component of immune surveillance that can be abrogated by somatic LOH of 
      the human leukocyte antigen class I (HLA-I) locus. To understand the role of 
      HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset 
      of 83,644 patient samples, a small subset of which had treatment outcomes with 
      immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly 
      had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was 
      frequent at intermediate TMB, yet prevalence decreased above 30 
      mutations/megabase, suggesting highly mutated tumors require alternate immune 
      evasion mechanisms. In ICI-treated patients with nonsquamous non-small cell lung 
      cancer, HLA-I LOH was a significant negative predictor of overall survival. 
      Survival prediction improved when combined with TMB, suggesting TMB with HLA-I 
      LOH may better identify patients likely to benefit from ICIs. SIGNIFICANCE: This 
      work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected 
      "Goldilocks" relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH 
      as a significant negative predictor of outcomes after ICI treatment. These data 
      informed a combined predictor of outcomes after ICI and have implications for 
      tumor vaccine development.This article is highlighted in the In This Issue 
      feature, p. 211.
CI  - (c)2020 American Association for Cancer Research.
FAU - Montesion, Meagan
AU  - Montesion M
AUID- ORCID: 0000-0001-9155-556X
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Murugesan, Karthikeyan
AU  - Murugesan K
AUID- ORCID: 0000-0002-2275-1126
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Jin, Dexter X
AU  - Jin DX
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Sharaf, Radwa
AU  - Sharaf R
AUID- ORCID: 0000-0002-5214-380X
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Sanchez, Nora
AU  - Sanchez N
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Guria, Ameet
AU  - Guria A
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Minker, Max
AU  - Minker M
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Li, Gerald
AU  - Li G
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Fisher, Virginia
AU  - Fisher V
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Sokol, Ethan S
AU  - Sokol ES
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Pavlick, Dean C
AU  - Pavlick DC
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Moore, Jay A
AU  - Moore JA
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Braly, Alan
AU  - Braly A
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Singal, Gaurav
AU  - Singal G
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Fabrizio, David
AU  - Fabrizio D
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Comment, Leah A
AU  - Comment LA
AUID- ORCID: 0000-0002-4160-0323
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Rizvi, Naiyer A
AU  - Rizvi NA
AUID- ORCID: 0000-0002-1134-7494
AD  - Columbia University Irving Medical Center, New York, New York.
FAU - Alexander, Brian M
AU  - Alexander BM
AUID- ORCID: 0000-0003-3903-9175
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Frampton, Garrett M
AU  - Frampton GM
AUID- ORCID: 0000-0002-2361-2750
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Hegde, Priti S
AU  - Hegde PS
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts.
FAU - Albacker, Lee A
AU  - Albacker LA
AUID- ORCID: 0000-0002-5070-1783
AD  - Foundation Medicine, Inc., Cambridge, Massachusetts. 
      lalbacker@foundationmedicine.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201030
PL  - United States
TA  - Cancer Discov
JT  - Cancer discovery
JID - 101561693
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (HLA Antigens)
RN  - 0 (Immune Checkpoint Inhibitors)
SB  - IM
MH  - Biomarkers, Tumor/genetics
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy
MH  - HLA Antigens/*genetics
MH  - Humans
MH  - Immune Checkpoint Inhibitors/*therapeutic use
MH  - Lung Neoplasms/*drug therapy
MH  - Mutation
MH  - Tumor Escape
EDAT- 2020/11/01 06:00
MHDA- 2022/01/15 06:00
CRDT- 2020/10/31 05:30
PHST- 2020/05/18 00:00 [received]
PHST- 2020/09/14 00:00 [revised]
PHST- 2020/10/27 00:00 [accepted]
PHST- 2020/11/01 06:00 [pubmed]
PHST- 2022/01/15 06:00 [medline]
PHST- 2020/10/31 05:30 [entrez]
AID - 2159-8290.CD-20-0672 [pii]
AID - 10.1158/2159-8290.CD-20-0672 [doi]
PST - ppublish
SO  - Cancer Discov. 2021 Feb;11(2):282-292. doi: 10.1158/2159-8290.CD-20-0672. Epub 
      2020 Oct 30.