Online citations, reference lists, and bibliographies.
← Back to Search

PD-L1 Expression Is Associated With Tumor-infiltrating T Cells And Favorable Prognosis In High-grade Serous Ovarian Cancer.

J. R. Webb, K. Milne, David R. Kroeger, B. Nelson
Published 2016 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
OBJECTIVE As a negative regulator of T cells, Programmed Death Ligand 1 (PD-L1) is both an indicator and inhibitor of anti-tumor immune responses, which has led to confusion about its prognostic significance. We investigated the primary source of PD-L1 expression in epithelial ovarian cancer and its relationship to tumor-infiltrating lymphocytes (TIL) and associated gene products. METHODS Tissue microarrays containing high-grade serous carcinomas (HGSC) and endometrioid, clear cell and mucinous ovarian cancers from optimally debulked patients were assessed by immunohistochemistry for expression of PD-L1 and other markers (CD68, CD3, CD8, PD-1, CD103, FoxP3 and CD25). The Cancer Genome Atlas was interrogated for associations between PD-L1 expression and immune-related transcriptional and genomic features of HGSC. RESULTS PD-L1 was primarily expressed by tumor-associated CD68(+) macrophages rather than tumor cells. PD-L1(+) cells frequently co-localized with CD8, CD4 and PD-1(+) TIL, CD25(+)FoxP3(+) Tregs, and other TIL subsets. PD-L1(+) cells were prognostically favorable in HGSC. Moreover, the presence of both PD-L1(+) cells and CD8 TIL was associated with better prognosis than CD8 TIL alone. PD-L1 gene expression was independent of BRCA status. At the transcriptional level, PD-L1 was associated with both cytolytic (granzyme B, T-bet and IFN-γ) and suppressive (PD-1, CTLA-4, LAG3 and IDO-1) gene products. CONCLUSIONS PD-L1 is primarily expressed by macrophages in ovarian cancer and is strongly associated with both cytolytic and regulatory TIL subsets, resulting in a net positive association with survival. Tumors containing PD-L1(+) macrophages appear caught in an immunological stalemate that may require multi-pronged immunotherapy to alleviate.
This paper references
10.1158/1078-0432.CCR-13-1877
Tumor-Infiltrating Lymphocytes Expressing the Tissue Resident Memory Marker CD103 Are Associated with Increased Survival in High-Grade Serous Ovarian Cancer
J. R. Webb (2013)
10.1200/JCO.2015.33.15_SUPPL.5509
Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial.
M. Disis (2015)
10.1200/JCO.2015.62.3397
Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer.
J. Hamanishi (2015)
10.1038/modpathol.2008.191
Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss
B. Clarke (2009)
10.1158/2326-6066.CIR-14-0146
CD25 Identifies a Subset of CD4+FoxP3− TIL That Are Exhausted Yet Prognostically Favorable in Human Ovarian Cancer
R. deLeeuw (2014)
10.1016/j.coph.2015.05.011
PD-1/PD-L1 inhibitors.
J. Sunshine (2015)
10.1371/journal.pone.0006412
Systematic Analysis of Immune Infiltrates in High-Grade Serous Ovarian Cancer Reveals CD20, FoxP3 and TIA-1 as Positive Prognostic Factors
K. Milne (2009)
10.1016/j.coi.2015.02.004
New insights into tumor immunity revealed by the unique genetic and genomic aspects of ovarian cancer.
B. Nelson (2015)
10.1056/NEJMoa1200694
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
J. Brahmer (2012)
10.1038/nature13954
PD-1 blockade induces responses by inhibiting adaptive immune resistance
P. Tumeh (2014)
10.1158/0008-5472.CAN-15-0255
Classifying Cancers Based on T-cell Infiltration and PD-L1.
M. Teng (2015)
10.1073/pnas.0611533104
Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer
J. Hamanishi (2007)
10.1126/science.aaa4971
Neoantigens in cancer immunotherapy
T. Schumacher (2015)
10.1111/j.1600-065X.2009.00767.x
PD‐1 signaling in primary T cells
J. Riley (2009)
10.1158/2326-6066.CIR-14-0239
PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer
J. R. Webb (2015)
10.1038/ni.2762
A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application
T. Okazaki (2013)
10.1126/scitranslmed.3003689
Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape
J. Taube (2012)
10.1016/j.immuni.2013.06.014
Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance.
L. Zitvogel (2013)
10.1158/1078-0432.CCR-15-0244
Differential Expression of Immune-Regulatory Genes Associated with PD-L1 Display in Melanoma: Implications for PD-1 Pathway Blockade
J. Taube (2015)
10.1016/j.lungcan.2015.05.007
PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma.
W. Cooper (2015)
10.1038/nature10166
Integrated Genomic Analyses of Ovarian Carcinoma
D. Bell (2011)
10.1002/cncr.25747
Overall survival and PD‐L1 expression in metastasized malignant melanoma
J. Gadiot (2011)
10.1016/j.cllc.2015.03.008
Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of Programmed Death-Ligand 1 Expression in Non--Small-Cell Lung Cancer.
S. Kitazono (2015)
10.18632/ONCOTARGET.4378
Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1
Z. Gatalica (2015)
10.1101/gr.165985.113
Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival.
Scott D Brown (2014)
10.1158/0008-5472.CAN-12-2384
Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma.
Sofia Lyford-Pike (2013)
10.1016/j.it.2015.02.008
Overcoming T cell exhaustion in infection and cancer.
Kristen E. Pauken (2015)
10.1172/JCI73639
PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors.
A. Gros (2014)
10.1200/JCO.2015.33.15_SUPPL.5510
Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: Interim results from a phase Ib study.
A. Varga (2015)
10.1158/2326-6066.CIR-15-0116
PD-L1 Antibodies to Its Cytoplasmic Domain Most Clearly Delineate Cell Membranes in Immunohistochemical Staining of Tumor Cells
K. Mahoney (2015)
10.4049/jimmunol.181.10.6738
The Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Induce the Expression of Programmed Death-1 and Its Ligands
A. Kinter (2008)
10.18632/oncotarget.6429
Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma
S. Darb-Esfahani (2016)
10.1038/nature14011
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
R. Herbst (2014)
10.1182/blood-2010-05-282780
Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.
M. Green (2010)
10.1158/2326-6066.CIR-14-0133
PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer
Hallie Wimberly (2014)
10.1002/eji.201040979
PD‐L1 expression on tolerogenic APCs is controlled by STAT‐3
S. Wölfle (2011)
10.1158/1078-0432.CCR-10-2660
Programmed Death Ligand 1 Is Expressed by Non–Hodgkin Lymphomas and Inhibits the Activity of Tumor-Associated T Cells
D. Andorsky (2011)
10.1371/journal.pmed.0050232
Ovarian Carcinoma Subtypes Are Different Diseases: Implications for Biomarker Studies
M. Köbel (2008)
10.1084/jem.20131916
PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation
M. Noman (2014)
10.1158/1078-0432.CCR-13-3271
Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy
J. Taube (2014)



This paper is referenced by
10.1038/s41598-021-83276-z
Differential expression of PD-L1 between primary and metastatic epithelial ovarian cancer and its clinico-pathological correlation
S. K. Parvathareddy (2021)
10.1186/s13048-019-0512-6
Prognostic effect of programmed death-ligand 1 (PD-L1) in ovarian cancer: a systematic review, meta-analysis and bioinformatics study
L. Wang (2019)
10.1186/s12967-020-02389-7
Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1
Karolina Okła (2020)
10.1002/cncr.31761
The antitumor effects of entinostat in ovarian cancer require adaptive immunity
H. Smith (2018)
10.1080/2162402X.2017.1412029
Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
Manja Idorn (2018)
10.3389/fonc.2019.01015
Soluble Programmed Death Receptor Ligands sPD-L1 and sPD-L2 as Liquid Biopsy Markers for Prognosis and Platinum Response in Epithelial Ovarian Cancer
P. Buderath (2019)
10.1016/j.pharmthera.2018.09.008
Targeting Programmed Cell Death ‐1 (PD‐1) and Ligand (PD‐L1): A new era in cancer active immunotherapy
A. Constantinidou (2019)
10.1038/s41388-018-0303-3
Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations
Ioannis Zerdes (2018)
10.3390/cancers12123828
Changes in the Tumor Immune Microenvironment during Disease Progression in Patients with Ovarian Cancer
M. Westergaard (2020)
10.1136/ijgc-2018-000065
Emerging biomarkers in ovarian granulosa cell tumors
A. Mills (2019)
10.1016/j.celrep.2016.08.032
BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.
H. Zhu (2016)
10.3390/cancers12030561
Factors in Oncogenesis: Viral Infections in Ovarian Cancer
S. Pathak (2020)
10.1007/s00262-019-02434-5
VISTA expression is associated with a favorable prognosis in patients with high-grade serous ovarian cancer
Liju Zong (2019)
10.1016/j.ygyno.2017.03.509
NY-ESO-1 expression predicts an aggressive phenotype of ovarian cancer.
J. Szender (2017)
10.1111/cas.13065
An IL‐27/Stat3 axis induces expression of programmed cell death 1 ligands (PD‐L1/2) on infiltrating macrophages in lymphoma
Hasita Horlad (2016)
10.1016/j.archoralbio.2018.09.017
Immune response and evasion mechanisms in lip carcinogenesis: An immunohistochemical study.
M. L. D. S. Lopes (2019)
10.1007/s00428-020-02751-6
PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma
Laura Martin de la Fuente (2020)
10.1016/j.ygyno.2018.07.025
Patient inflammatory status and CD4+/CD8+ intraepithelial tumor lymphocyte infiltration are predictors of outcomes in high-grade serous ovarian cancer.
M. Pinto (2018)
10.1186/s13048-017-0304-9
Characterization of ovarian clear cell carcinoma using target drug-based molecular biomarkers: implications for personalized cancer therapy
M. Li (2017)
10.3390/cancers10080266
Targeting the Microenvironment in High Grade Serous Ovarian Cancer
Nkechiyere G. Nwani (2018)
10.1016/BS.ACR.2019.05.001
Expression of costimulatory and inhibitory receptors in FoxP3+ regulatory T cells within the tumor microenvironment: Implications for combination immunotherapy approaches.
Aras Toker (2019)
10.1186/s40661-018-0063-3
Response to pembrolizumab in a heavily treated patient with metastatic ovarian carcinosarcoma
Graziela Zibetti Dal Molin (2018)
10.1097/IGC.0000000000001115
Novel Therapeutics for Ovarian Cancer: The 11th Biennial Rivkin Center Ovarian Cancer Research Symposium
N. Johnson (2017)
10.1016/j.surg.2018.04.086
Expression of programmed death ligand 1 and 2 in adrenocortical cancer tissues: An exploratory study
J. F. Tierney (2019)
10.1038/modpathol.2017.67
Mismatch repair status and PD-L1 expression in clear cell carcinomas of the ovary and endometrium
B. C. Willis (2017)
10.1111/cas.14340
Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE‐100
S. Nishio (2020)
10.3892/ol.2018.9059
Expression of V-domain immunoglobulin suppressor of T cell activation is associated with the advanced stage and presence of lymph node metastasis in ovarian cancer
H. Liao (2018)
10.21037/jgo.2017.06.15
Radiation generates an abscopal response and complete resolution of metastatic squamous cell carcinoma of the anal canal: a case report.
Moss Bruton Joe (2017)
10.1080/2162402X.2016.1269047
Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma
C. Deng (2017)
10.3390/ijms17071169
Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?
G. Mittica (2016)
10.1186/s40661-016-0033-6
The role of immune checkpoint inhibition in the treatment of ovarian cancer
S. Gaillard (2016)
10.1136/ijgc-2019-000609
Prognostic significance of PD-1 and PD-L1 positive tumor-infiltrating immune cells in ovarian carcinoma
P. Buderath (2019)
See more
Semantic Scholar Logo Some data provided by SemanticScholar