PMID- 29942303
OWN - NLM
STAT- MEDLINE
DCOM- 20190813
LR  - 20230926
IS  - 1664-3224 (Print)
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 9
DP  - 2018
TI  - The Prognostic Value of Immune Factors in the Tumor Microenvironment of Penile 
      Squamous Cell Carcinoma.
PG  - 1253
LID - 10.3389/fimmu.2018.01253 [doi]
LID - 1253
AB  - The host's immune system plays a pivotal role in many tumor types, including 
      squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators 
      for lymph node metastases (LNM) and disease-specific survival (DSS) in penile 
      SCC. For this retrospective observational cohort study, penile SCC patients 
      (n = 213) treated in the Netherlands Cancer Institute, were selected if 
      sufficient formalin-fixed, paraffin-embedded tumor material was available. 
      Analysis included previously described high-risk human papilloma virus (hrHPV) 
      status, immunohistochemical scores for classical and non-classical human 
      leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, 
      and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory 
      T-cells. Clinicopathological characteristics and extended follow-up were also 
      included. Regression analyses investigated relationships of the immune parameters 
      with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, 
      CD163(+) macrophage infiltration, non-classical HLA class I upregulation, and low 
      stromal CD8(+) T-cell infiltration were all associated with LNM. In the 
      multivariable model, only tumor PD-L1 expression remained a significant predictor 
      for LNM (odds ratio (OR) 2.8, p = 0.05). hrHPV negativity and diffuse PD-L1 
      tumor-cell expression were significantly associated with poor DSS and remained so 
      upon correction for clinical parameters [hazard ratio (HR) 9.7, p < 0.01 and HR 
      2.8, p = 0.03]. The only immune factor with different expression in HPV(+) and 
      HPV(-) tumors was PD-L1, with higher PD-L1 expression in the latter (p = 0.03). 
      In the HPV(-) cohort (n = 158), LNM were associated with diffuse PD-L1 tumor-cell 
      expression, high intratumoral CD163(+) macrophage infiltration, and low number of 
      stromal CD8(+) T-cells. The first two parameters were also linked to DSS. In the 
      multivariable regression model, diffuse PD-L1 expression remained significantly 
      unfavorable for DSS (HR 5.0, p < 0.01). These results emphasize the complexity of 
      the tumor microenvironment in penile cancer and point toward several possible 
      immunotherapy targets. Here described immune factors can aid risk-stratification 
      and should be evaluated in clinical immunotherapy studies to ultimately lead to 
      patient tailored treatment.
FAU - Ottenhof, Sarah Rosanne
AU  - Ottenhof SR
AD  - Department of Urology, Netherlands Cancer Institute, Amsterdam, Netherlands.
FAU - Djajadiningrat, Rosa Sanne
AU  - Djajadiningrat RS
AD  - Department of Urology, Netherlands Cancer Institute, Amsterdam, Netherlands.
AD  - Department of Urology, HagaZiekenhuis, Hague, Netherlands.
FAU - Thygesen, Helene Hoegsbro
AU  - Thygesen HH
AD  - Department of Biometrics, Netherlands Cancer Institute, Amsterdam, Netherlands.
AD  - Statistics, Department of Conservation, Hamilton, New Zealand.
FAU - Jakobs, Pamela Josephine
AU  - Jakobs PJ
AD  - Department of Urology, Netherlands Cancer Institute, Amsterdam, Netherlands.
FAU - Jozwiak, Katarzyna
AU  - Jozwiak K
AD  - Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, 
      Amsterdam, Netherlands.
FAU - Heeren, Anne Marijne
AU  - Heeren AM
AD  - Center for Gynecologic Oncology Amsterdam (CGOA), VU University Medical Center, 
      Amsterdam, Netherlands.
FAU - de Jong, Jeroen
AU  - de Jong J
AD  - Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
FAU - Sanders, Joyce
AU  - Sanders J
AD  - Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
FAU - Horenblas, Simon
AU  - Horenblas S
AD  - Department of Urology, Netherlands Cancer Institute, Amsterdam, Netherlands.
FAU - Jordanova, Ekaterina Straschimirova
AU  - Jordanova ES
AD  - Center for Gynecologic Oncology Amsterdam (CGOA), VU University Medical Center, 
      Amsterdam, Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20180611
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Biomarkers)
RN  - 0 (CD274 protein, human)
RN  - 0 (Immunologic Factors)
MH  - Aged
MH  - B7-H1 Antigen/genetics/metabolism
MH  - Biomarkers
MH  - Carcinoma, Squamous Cell/*diagnosis/*immunology
MH  - Follow-Up Studies
MH  - Humans
MH  - Immunologic Factors
MH  - Lymphocytes, Tumor-Infiltrating/immunology/metabolism
MH  - Macrophages/immunology/metabolism
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - Netherlands
MH  - Odds Ratio
MH  - Papillomavirus Infections/classification/genetics
MH  - Penile Neoplasms/*diagnosis/*immunology
MH  - Prognosis
MH  - T-Lymphocytes, Cytotoxic
MH  - Tumor Microenvironment/*immunology
PMC - PMC6004546
OTO - NOTNLM
OT  - B7-H1
OT  - HPV
OT  - T-cells
OT  - immune escape
OT  - microenvironment
OT  - penile cancer
OT  - programmed death ligand-1
OT  - squamous cell carcinoma
EDAT- 2018/06/27 06:00
MHDA- 2018/06/27 06:01
PMCR- 2018/01/01
CRDT- 2018/06/27 06:00
PHST- 2018/03/26 00:00 [received]
PHST- 2018/05/18 00:00 [accepted]
PHST- 2018/06/27 06:00 [entrez]
PHST- 2018/06/27 06:00 [pubmed]
PHST- 2018/06/27 06:01 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2018.01253 [doi]
PST - epublish
SO  - Front Immunol. 2018 Jun 11;9:1253. doi: 10.3389/fimmu.2018.01253. eCollection 
      2018.