PMID- 33602682
OWN - NLM
STAT- MEDLINE
DCOM- 20220316
LR  - 20220716
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 27
IP  - 10
DP  - 2021 May 15
TI  - Spatial Analysis and Clinical Significance of HLA Class-I and Class-II Subunit 
      Expression in Non-Small Cell Lung Cancer.
PG  - 2837-2847
LID - 10.1158/1078-0432.CCR-20-3655 [doi]
AB  - PURPOSE: To analyze the distribution, associated immune contexture, and clinical 
      significance of human leukocyte antigen (HLA) class-I and HLA class-II subunits 
      in non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Using spatially 
      resolved and quantitative multiplexed immunofluorescence we studied the 
      tumor/stromal tissue distribution, cancer cell-specific defects, and 
      clinicopathologic/survival associations of beta2 microglobulin (beta2M), HLA-A, and 
      HLA-B,-C heavy chains, as well as HLA class-II beta chain in >700 
      immunotherapy-naive NSCLCs from four independent cohorts. Genomic analysis of HLA 
      genes in NSCLC was performed using two publicly available cohorts. RESULTS: 
      Cancer cell-specific downregulation of HLA markers was identified in 30.4% of 
      cases. beta2M was downregulated in 9.8% (70/714), HLA-A in 9% (65/722), HLA-B,-C in 
      12.1% (87/719), and HLA class-II in 17.7% (127/717) of evaluable samples. 
      Concurrent downregulation of beta2M, HLA-B,-C, and HLA class-II was commonly 
      identified. Deleterious mutations in HLA genes were detected in <5% of lung 
      malignancies. Tumors with cancer cell-specific beta2M downregulation displayed 
      reduced T cells and increased natural killer (NK)-cell infiltration. Samples with 
      cancer cell HLA-A downregulation displayed modest increase in CD8(+) T cells and 
      NK-cell infiltration. Samples with cancer cell-selective HLA-B,-C or HLA class-II 
      downregulation displayed reduced T cells and NK-cell infiltration. There was 
      limited association of the markers with clinicopathologic variables and KRAS/EGFR 
      mutations. Cancer cell-selective downregulation of the HLA subunits was 
      associated with shorter overall survival. CONCLUSIONS: Our results reveal 
      frequent and differential defects in HLA class-I and HLA class-II protein subunit 
      expression in immunotherapy-naive NSCLCs associated with distinct tumor 
      microenvironment composition and patient survival.
CI  - (c)2021 American Association for Cancer Research.
FAU - Datar, Ila J
AU  - Datar IJ
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut.
FAU - Hauc, Sacha C
AU  - Hauc SC
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut.
FAU - Desai, Shruti
AU  - Desai S
AUID- ORCID: 0000-0002-5234-5890
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut.
FAU - Gianino, Nicole
AU  - Gianino N
AUID- ORCID: 0000-0003-1919-5920
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut.
FAU - Henick, Brian
AU  - Henick B
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut.
AD  - Medical Oncology, Columbia University Medical Center, New York, New York.
FAU - Liu, Yuting
AU  - Liu Y
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut.
FAU - Syrigos, Kostas
AU  - Syrigos K
AD  - Oncology Unit, Department of Medicine, Athens University, Athens, Greece.
FAU - Rimm, David L
AU  - Rimm DL
AUID- ORCID: 0000-0001-5820-4397
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut.
FAU - Kavathas, Paula
AU  - Kavathas P
AD  - Laboratory Medicine and Immunobiology, Yale School of Medicine, New Haven, 
      Connecticut.
FAU - Ferrone, Soldano
AU  - Ferrone S
AUID- ORCID: 0000-0003-2900-8834
AD  - Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
FAU - Schalper, Kurt A
AU  - Schalper KA
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut. kurt.schalper@yale.edu.
LA  - eng
GR  - R03 CA219603/CA/NCI NIH HHS/United States
GR  - R01 DE028172/DE/NIDCR NIH HHS/United States
GR  - R03 CA253319/CA/NCI NIH HHS/United States
GR  - P30 CA016359/CA/NCI NIH HHS/United States
GR  - R37 CA245154/CA/NCI NIH HHS/United States
GR  - P50 CA196530/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210218
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Histocompatibility Antigens Class II)
SB  - IM
MH  - *Alleles
MH  - Carcinoma, Non-Small-Cell Lung/diagnosis/*genetics/mortality
MH  - Computational Biology/methods
MH  - DNA Mutational Analysis
MH  - Fluorescent Antibody Technique/methods/standards
MH  - *Gene Expression Regulation, Neoplastic
MH  - Histocompatibility Antigens Class I/*genetics/immunology/metabolism
MH  - Histocompatibility Antigens Class II/*genetics/immunology/metabolism
MH  - Humans
MH  - Lung Neoplasms/diagnosis/*genetics/mortality
MH  - Mutation
MH  - Prognosis
PMC - PMC8734284
MID - NIHMS1677039
EDAT- 2021/02/20 06:00
MHDA- 2022/03/17 06:00
PMCR- 2022/01/06
CRDT- 2021/02/19 05:54
PHST- 2020/09/15 00:00 [received]
PHST- 2020/11/17 00:00 [revised]
PHST- 2021/02/15 00:00 [accepted]
PHST- 2021/02/20 06:00 [pubmed]
PHST- 2022/03/17 06:00 [medline]
PHST- 2021/02/19 05:54 [entrez]
PHST- 2022/01/06 00:00 [pmc-release]
AID - 1078-0432.CCR-20-3655 [pii]
AID - 10.1158/1078-0432.CCR-20-3655 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2021 May 15;27(10):2837-2847. doi: 
      10.1158/1078-0432.CCR-20-3655. Epub 2021 Feb 18.