PMID- 27837027
OWN - NLM
STAT- MEDLINE
DCOM- 20180330
LR  - 20181113
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 113
IP  - 48
DP  - 2016 Nov 29
TI  - Association of PD-1/PD-L axis expression with cytolytic activity, mutational
      load, and prognosis in melanoma and other solid tumors.
PG  - E7769-E7777
AB  - Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1)
      checkpoint blockade has led to remarkable and durable objective responses in a
      number of different tumor types. A better understanding of factors associated
      with the PD-1/PD-L axis expression is desirable, as it informs their potential
      role as prognostic and predictive biomarkers and may suggest rational treatment
      combinations. In the current study, we analyzed PD-L1, PD-L2, PD-1, and cytolytic
      activity (CYT) expression, as well as mutational density from melanoma and eight 
      other solid tumor types using The Cancer Genome Atlas database. We found that in 
      some tumor types, PD-L2 expression is more closely linked to Th1/IFNG expression 
      and PD-1 and CD8 signaling than PD-L1 In contrast, mutational load was not
      correlated with a Th1/IFNG gene signature in any tumor type. PD-L1, PD-L2, PD-1, 
      CYT expression, and mutational density are all positive prognostic features in
      melanoma, and conditional inference modeling revealed PD-1/CYT expression (i.e., 
      an inflamed tumor microenvironment) as the most impactful feature, followed by
      mutational density. This study elucidates the highly interdependent nature of
      these parameters, and also indicates that future biomarkers for anti-PD-1/PD-L1
      will benefit from tumor-type-specific, integrated, mRNA, protein, and genomic
      approaches.
FAU - Danilova, Ludmila
AU  - Danilova L
AUID- ORCID: 0000-0003-2813-3094
AD  - Department of Oncology, The Johns Hopkins University School of Medicine, Sidney
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
AD  - Vavilov Institute of General Genetics, Russian Academy of Science, Moscow,
      Russia, 119333.
AD  - The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, 
      Baltimore, MD 21287.
FAU - Wang, Hao
AU  - Wang H
AD  - Department of Oncology, The Johns Hopkins University School of Medicine, Sidney
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
FAU - Sunshine, Joel
AU  - Sunshine J
AD  - Department of Dermatology, The Johns Hopkins University School of Medicine,
      Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
FAU - Kaunitz, Genevieve J
AU  - Kaunitz GJ
AD  - Department of Dermatology, The Johns Hopkins University School of Medicine,
      Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
FAU - Cottrell, Tricia R
AU  - Cottrell TR
AD  - Department of Pathology, The Johns Hopkins University School of Medicine, Sidney 
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
FAU - Xu, Haiying
AU  - Xu H
AD  - Department of Dermatology, The Johns Hopkins University School of Medicine,
      Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
FAU - Esandrio, Jessica
AU  - Esandrio J
AD  - Department of Dermatology, The Johns Hopkins University School of Medicine,
      Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
FAU - Anders, Robert A
AU  - Anders RA
AD  - Department of Oncology, The Johns Hopkins University School of Medicine, Sidney
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
AD  - The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, 
      Baltimore, MD 21287.
AD  - Department of Pathology, The Johns Hopkins University School of Medicine, Sidney 
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
FAU - Cope, Leslie
AU  - Cope L
AD  - Department of Oncology, The Johns Hopkins University School of Medicine, Sidney
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
AD  - The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, 
      Baltimore, MD 21287.
FAU - Pardoll, Drew M
AU  - Pardoll DM
AD  - Department of Oncology, The Johns Hopkins University School of Medicine, Sidney
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
AD  - The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, 
      Baltimore, MD 21287.
FAU - Drake, Charles G
AU  - Drake CG
AD  - Department of Oncology, The Johns Hopkins University School of Medicine, Sidney
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
AD  - The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, 
      Baltimore, MD 21287.
AD  - The Brady Urological Institute, The Johns Hopkins University School of Medicine, 
      Baltimore, MD 21287.
FAU - Taube, Janis M
AU  - Taube JM
AD  - Department of Oncology, The Johns Hopkins University School of Medicine, Sidney
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287; jtaube1@jhmi.edu.
AD  - The Bloomberg-Kimmel Institute, The Johns Hopkins University School of Medicine, 
      Baltimore, MD 21287.
AD  - Department of Dermatology, The Johns Hopkins University School of Medicine,
      Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
AD  - Department of Pathology, The Johns Hopkins University School of Medicine, Sidney 
      Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
LA  - eng
GR  - P30 CA006973/CA/NCI NIH HHS/United States
GR  - R01 CA142779/CA/NCI NIH HHS/United States
GR  - T32 CA193145/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 - 20161111
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD274 protein, human)
RN  - 0 (PDCD1 protein, human)
RN  - 0 (PDCD1LG2 protein, human)
RN  - 0 (Programmed Cell Death 1 Ligand 2 Protein)
RN  - 0 (Programmed Cell Death 1 Receptor)
SB  - IM
MH  - Adenocarcinoma/genetics/metabolism/mortality
MH  - B7-H1 Antigen/*genetics/metabolism
MH  - Colonic Neoplasms/genetics/metabolism/mortality
MH  - DNA Mutational Analysis
MH  - Gene Expression
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Melanoma/*genetics/metabolism/mortality
MH  - Mutation
MH  - Mutation Rate
MH  - Prognosis
MH  - Programmed Cell Death 1 Ligand 2 Protein/*genetics/metabolism
MH  - Programmed Cell Death 1 Receptor/*genetics/metabolism
MH  - Proportional Hazards Models
MH  - Skin Neoplasms/*genetics/metabolism/mortality
PMC - PMC5137776
OTO - NOTNLM
OT  - *PD-1
OT  - *PD-L1
OT  - *PD-L2
OT  - *melanoma
OT  - *mutational load
COIS- R.A.A. is a compensated consultant for Adaptive Biotech. D.M.P. has received
      research grants from Bristol-Myers Squibb and Potenza Therapeutics; consults for 
      Amgen, Five Prime Therapeutics, GlaxoSmithKline, Jounce Therapeutics, MedImmune, 
      Merck, Pfizer, Potenza Therapeutics, and Sanofi; owns stock options in Jounce and
      Potenza; and receives patent royalties through his institution, from
      Bristol-Myers Squibb, and Potenza. C.G.D. is a self-compensated consultant for
      Bristol-Myers Squibb, AstraZeneca/Medimmune, Roche/Genentech, Potenza
      Therapeutics, and Tizona Therapeutics; and has patents licensed by Bristol-Myers 
      Squibb, AstraZeneca/Medimmune, and Potenza Therapeutics. J.M.T. is a compensated 
      consultant for Bristol-Myers Squibb, AstraZeneca/Medimmune, and Merck.
EDAT- 2016/11/12 06:00
MHDA- 2018/03/31 06:00
CRDT- 2016/11/13 06:00
PHST- 2016/11/12 06:00 [pubmed]
PHST- 2018/03/31 06:00 [medline]
PHST- 2016/11/13 06:00 [entrez]
AID - 1607836113 [pii]
AID - 10.1073/pnas.1607836113 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7769-E7777. doi:
      10.1073/pnas.1607836113. Epub 2016 Nov 11.