The prognostic value of immune factors in the tumor microenvironment of penile squamous cell carcinoma

Sarah Rosanne Ottenhof, Rosa Sanne Djajadiningrat, Helene Hoegsbro Thygesen, Pamela Josephine Jakobs, Katarzyna Józwiak, Anne Marijne Heeren, Jeroen de Jong, Joyce Sanders, Simon Horenblas, Ekaterina Straschimirova Jordanova

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number1253
JournalFrontiers in Immunology
Volume9
Issue numberJUN
DOIs
Publication statusPublished - 11 Jun 2018

Cite this

Ottenhof, Sarah Rosanne ; Djajadiningrat, Rosa Sanne ; Thygesen, Helene Hoegsbro ; Jakobs, Pamela Josephine ; Józwiak, Katarzyna ; Heeren, Anne Marijne ; de Jong, Jeroen ; Sanders, Joyce ; Horenblas, Simon ; Jordanova, Ekaterina Straschimirova. / The prognostic value of immune factors in the tumor microenvironment of penile squamous cell carcinoma. In: Frontiers in Immunology. 2018 ; Vol. 9, No. JUN.
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title = "The prognostic value of immune factors in the tumor microenvironment of penile squamous cell carcinoma",
abstract = "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.",
keywords = "B7-H1, HPV, Immune escape, Microenvironment, Penile cancer, Programmed death ligand-1, Squamous cell carcinoma, T-cells",
author = "Ottenhof, {Sarah Rosanne} and Djajadiningrat, {Rosa Sanne} and Thygesen, {Helene Hoegsbro} and Jakobs, {Pamela Josephine} and Katarzyna J{\'o}zwiak and Heeren, {Anne Marijne} and {de Jong}, Jeroen and Joyce Sanders and Simon Horenblas and Jordanova, {Ekaterina Straschimirova}",
year = "2018",
month = "6",
day = "11",
doi = "10.3389/fimmu.2018.01253",
language = "English",
volume = "9",
journal = "Frontiers in Immunology: Molecular Innate Immunity",
issn = "1664-3224",
publisher = "Frontiers Media S.A.",
number = "JUN",

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Ottenhof, SR, Djajadiningrat, RS, Thygesen, HH, Jakobs, PJ, Józwiak, K, Heeren, AM, de Jong, J, Sanders, J, Horenblas, S & Jordanova, ES 2018, 'The prognostic value of immune factors in the tumor microenvironment of penile squamous cell carcinoma' Frontiers in Immunology, vol. 9, no. JUN, 1253. https://doi.org/10.3389/fimmu.2018.01253

The prognostic value of immune factors in the tumor microenvironment of penile squamous cell carcinoma. / Ottenhof, Sarah Rosanne; Djajadiningrat, Rosa Sanne; Thygesen, Helene Hoegsbro; Jakobs, Pamela Josephine; Józwiak, Katarzyna; Heeren, Anne Marijne; de Jong, Jeroen; Sanders, Joyce; Horenblas, Simon; Jordanova, Ekaterina Straschimirova.

In: Frontiers in Immunology, Vol. 9, No. JUN, 1253, 11.06.2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The prognostic value of immune factors in the tumor microenvironment of penile squamous cell carcinoma

AU - Ottenhof, Sarah Rosanne

AU - Djajadiningrat, Rosa Sanne

AU - Thygesen, Helene Hoegsbro

AU - Jakobs, Pamela Josephine

AU - Józwiak, Katarzyna

AU - Heeren, Anne Marijne

AU - de Jong, Jeroen

AU - Sanders, Joyce

AU - Horenblas, Simon

AU - Jordanova, Ekaterina Straschimirova

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N2 - 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.

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.

KW - B7-H1

KW - HPV

KW - Immune escape

KW - Microenvironment

KW - Penile cancer

KW - Programmed death ligand-1

KW - Squamous cell carcinoma

KW - T-cells

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