Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix

Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but informat...

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Vydané v:	Modern pathology Ročník 29; číslo 7; s. 753 - 763
Hlavní autori:	Heeren, A Marijne, Punt, Simone, Bleeker, Maaike CG, Gaarenstroom, Katja N, van der Velden, Jacobus, Kenter, Gemma G, de Gruijl, Tanja D, Jordanova, Ekaterina S
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.07.2016 Elsevier Limited Nature Publishing Group
Predmet:	13/51 631/67/327 631/67/580/1884 Adenocarcinoma - metabolism Adenocarcinoma - mortality Adenocarcinoma - pathology Adult Aged Aged, 80 and over B7-H1 Antigen - metabolism Biomarkers, Tumor - metabolism Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - mortality Carcinoma, Squamous Cell - pathology Cell death Cervical cancer Cervix Disease-Free Survival Female Gynecology Human papillomavirus Humans Immunohistochemistry Laboratory Medicine Ligands Lymphatic system Macrophages - metabolism Macrophages - pathology Medical prognosis Medicine Medicine & Public Health Metastasis Middle Aged Obstetrics Oncology Original original-article Pathology Patients Phenotype Prognosis Survival Rate Tumors Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - mortality Uterine Cervical Neoplasms - pathology Young Adult Netherlands
ISSN:	0893-3952, 1530-0285, 1530-0285
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Abstract	Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n =156 and adenocarcinoma, n =49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n =96 and adenocarcinoma, n =31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P <0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival ( P =0.022) and disease-specific survival ( P =0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages ( P =0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors ( P =0.001 for squamous cell carcinoma and P =0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway.
AbstractList	Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n=156 and adenocarcinoma, n=49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n=96 and adenocarcinoma, n=31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P<0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival (P=0.022) and disease-specific survival (P=0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages (P=0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors (P=0.001 for squamous cell carcinoma and P=0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway. Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n=156 and adenocarcinoma, n=49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n=96 and adenocarcinoma, n=31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P<0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival (P=0.022) and disease-specific survival (P=0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages (P=0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors (P=0.001 for squamous cell carcinoma and P=0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway.Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n=156 and adenocarcinoma, n=49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n=96 and adenocarcinoma, n=31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P<0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival (P=0.022) and disease-specific survival (P=0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages (P=0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors (P=0.001 for squamous cell carcinoma and P=0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway. Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n =156 and adenocarcinoma, n =49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n =96 and adenocarcinoma, n =31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P <0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival ( P =0.022) and disease-specific survival ( P =0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages ( P =0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors ( P =0.001 for squamous cell carcinoma and P =0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway.
Author	Gaarenstroom, Katja N Jordanova, Ekaterina S de Gruijl, Tanja D van der Velden, Jacobus Kenter, Gemma G Punt, Simone Heeren, A Marijne Bleeker, Maaike CG
Author_xml	– sequence: 1 givenname: A Marijne surname: Heeren fullname: Heeren, A Marijne organization: Department of Obstetrics and Gynecology, Center for Gynecological Oncology Amsterdam (CGOA), VU University Medical Center, Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam – sequence: 2 givenname: Simone surname: Punt fullname: Punt, Simone organization: Department of Pathology, Leiden University Medical Center, Leiden – sequence: 3 givenname: Maaike CG surname: Bleeker fullname: Bleeker, Maaike CG organization: Department of Pathology, VU University Medical Center – sequence: 4 givenname: Katja N surname: Gaarenstroom fullname: Gaarenstroom, Katja N organization: Department of Gynecology, Leiden University Medical Center, Leiden – sequence: 5 givenname: Jacobus surname: van der Velden fullname: van der Velden, Jacobus organization: Department of Obstetrics and Gynecology, Center Gynecological Oncology Amsterdam (CGOA), Academic Medical Center – sequence: 6 givenname: Gemma G surname: Kenter fullname: Kenter, Gemma G organization: Department of Obstetrics and Gynecology, Center for Gynecological Oncology Amsterdam (CGOA), VU University Medical Center, Department of Obstetrics and Gynecology, Center Gynecological Oncology Amsterdam (CGOA), Academic Medical Center, Department of Gynecology, Center Gynecological Oncology Amsterdam (CGOA), Netherlands Cancer Institute—Antoni van Leeuwenhoek – sequence: 7 givenname: Tanja D surname: de Gruijl fullname: de Gruijl, Tanja D organization: Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam – sequence: 8 givenname: Ekaterina S surname: Jordanova fullname: Jordanova, Ekaterina S email: e.jordanova@vumc.nl organization: Department of Obstetrics and Gynecology, Center for Gynecological Oncology Amsterdam (CGOA), VU University Medical Center, Department of Pathology, Leiden University Medical Center, Leiden
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27056074$$D View this record in MEDLINE/PubMed
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Snippet	Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their...
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SubjectTerms	13/51 631/67/327 631/67/580/1884 Adenocarcinoma - metabolism Adenocarcinoma - mortality Adenocarcinoma - pathology Adult Aged Aged, 80 and over B7-H1 Antigen - metabolism Biomarkers, Tumor - metabolism Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - mortality Carcinoma, Squamous Cell - pathology Cell death Cervical cancer Cervix Disease-Free Survival Female Gynecology Human papillomavirus Humans Immunohistochemistry Laboratory Medicine Ligands Lymphatic system Macrophages - metabolism Macrophages - pathology Medical prognosis Medicine Medicine & Public Health Metastasis Middle Aged Obstetrics Oncology Original original-article Pathology Patients Phenotype Prognosis Survival Rate Tumors Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - mortality Uterine Cervical Neoplasms - pathology Young Adult
Title	Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix
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