Tumor-associated macrophages and the tumor immune microenvironment of primary and recurrent epithelial ovarian cancer

Research output: Contribution to journalArticle

Abstract

Tumor-infiltrating lymphocytes (TILs) are associated with better prognosis in newly diagnosed epithelial ovarian cancer (EOC), but clinical trials of immunotherapies in patients with heavily treated disease reveal limited activity. Understanding the tumor microenvironment (TME) of primary and recurrent EOC should guide future trials. Here, we evaluated the TME of paired primary and recurrent tumors (n = 17), and non-paired primary (n = 20) and recurrent (n = 15) tumors, for CD8+ T cells, FOXP3+ regulatory T cells (Tregs), CD68+ tumor-associated macrophages (TAMs), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1). CD8+ T cells were similar in primary and recurrent tumors, but Tregs were higher in recurrent tumors (P =.0210). Higher TAM density (≥5%) associated with higher Tregs (P =.001) and CD8+ T cells (P <.001) in recurrent tumors, but only with higher Tregs in primary tumors (P =.02). TAM-dense recurrent tumors expressed PD-L1 on tumor and immune cells, whereas TAM-dense primary tumors expressed PD-L1 predominantly on immune cells. In survival analyses, higher Tregs in primary tumors correlated with decreased time to first recurrence (17.0 versus 28.5 months, P =.022). Conversely, higher Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met versus 20.0 months, P =.022). TAM density did not affect patient survival. However, patients with increased TAMs at recurrence (n = 5) had longer OS from recurrence compared to patients without increased TAMs (n = 12) (56.0 versus 20.0 months); with the small sample size, this did not reach statistical significance (P =.074). Further characterization of the evolution of the TME is warranted.

Original languageEnglish (US)
Pages (from-to)135-147
Number of pages13
JournalHuman Pathology
Volume74
DOIs
StatePublished - Apr 1 2018

Fingerprint

Tumor Microenvironment
Macrophages
Neoplasms
Ovarian epithelial cancer
Recurrence
T-Lymphocytes
CD274 Antigen
Survival
Programmed Cell Death 1 Receptor
Cell Death
Ligands
Tumor-Infiltrating Lymphocytes

Keywords

  • CD8+ T cells
  • Ovarian cancer
  • PD-1/PD-L1
  • Regulatory T cells
  • Tumor-associated macrophages

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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title = "Tumor-associated macrophages and the tumor immune microenvironment of primary and recurrent epithelial ovarian cancer",
abstract = "Tumor-infiltrating lymphocytes (TILs) are associated with better prognosis in newly diagnosed epithelial ovarian cancer (EOC), but clinical trials of immunotherapies in patients with heavily treated disease reveal limited activity. Understanding the tumor microenvironment (TME) of primary and recurrent EOC should guide future trials. Here, we evaluated the TME of paired primary and recurrent tumors (n = 17), and non-paired primary (n = 20) and recurrent (n = 15) tumors, for CD8+ T cells, FOXP3+ regulatory T cells (Tregs), CD68+ tumor-associated macrophages (TAMs), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1). CD8+ T cells were similar in primary and recurrent tumors, but Tregs were higher in recurrent tumors (P =.0210). Higher TAM density (≥5{\%}) associated with higher Tregs (P =.001) and CD8+ T cells (P <.001) in recurrent tumors, but only with higher Tregs in primary tumors (P =.02). TAM-dense recurrent tumors expressed PD-L1 on tumor and immune cells, whereas TAM-dense primary tumors expressed PD-L1 predominantly on immune cells. In survival analyses, higher Tregs in primary tumors correlated with decreased time to first recurrence (17.0 versus 28.5 months, P =.022). Conversely, higher Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met versus 20.0 months, P =.022). TAM density did not affect patient survival. However, patients with increased TAMs at recurrence (n = 5) had longer OS from recurrence compared to patients without increased TAMs (n = 12) (56.0 versus 20.0 months); with the small sample size, this did not reach statistical significance (P =.074). Further characterization of the evolution of the TME is warranted.",
keywords = "CD8+ T cells, Ovarian cancer, PD-1/PD-L1, Regulatory T cells, Tumor-associated macrophages",
author = "Ojalvo, {Laureen S.} and Elizabeth Thompson and Tian-Li Wang and Meeker, {Alan Keith} and Shih, {Ie Ming} and {Nickles Fader}, {Amanda Nickles} and Cimino-Mathews, {Ashley M} and Emens, {Leisha A.}",
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T1 - Tumor-associated macrophages and the tumor immune microenvironment of primary and recurrent epithelial ovarian cancer

AU - Ojalvo, Laureen S.

AU - Thompson, Elizabeth

AU - Wang, Tian-Li

AU - Meeker, Alan Keith

AU - Shih, Ie Ming

AU - Nickles Fader, Amanda Nickles

AU - Cimino-Mathews, Ashley M

AU - Emens, Leisha A.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Tumor-infiltrating lymphocytes (TILs) are associated with better prognosis in newly diagnosed epithelial ovarian cancer (EOC), but clinical trials of immunotherapies in patients with heavily treated disease reveal limited activity. Understanding the tumor microenvironment (TME) of primary and recurrent EOC should guide future trials. Here, we evaluated the TME of paired primary and recurrent tumors (n = 17), and non-paired primary (n = 20) and recurrent (n = 15) tumors, for CD8+ T cells, FOXP3+ regulatory T cells (Tregs), CD68+ tumor-associated macrophages (TAMs), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1). CD8+ T cells were similar in primary and recurrent tumors, but Tregs were higher in recurrent tumors (P =.0210). Higher TAM density (≥5%) associated with higher Tregs (P =.001) and CD8+ T cells (P <.001) in recurrent tumors, but only with higher Tregs in primary tumors (P =.02). TAM-dense recurrent tumors expressed PD-L1 on tumor and immune cells, whereas TAM-dense primary tumors expressed PD-L1 predominantly on immune cells. In survival analyses, higher Tregs in primary tumors correlated with decreased time to first recurrence (17.0 versus 28.5 months, P =.022). Conversely, higher Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met versus 20.0 months, P =.022). TAM density did not affect patient survival. However, patients with increased TAMs at recurrence (n = 5) had longer OS from recurrence compared to patients without increased TAMs (n = 12) (56.0 versus 20.0 months); with the small sample size, this did not reach statistical significance (P =.074). Further characterization of the evolution of the TME is warranted.

AB - Tumor-infiltrating lymphocytes (TILs) are associated with better prognosis in newly diagnosed epithelial ovarian cancer (EOC), but clinical trials of immunotherapies in patients with heavily treated disease reveal limited activity. Understanding the tumor microenvironment (TME) of primary and recurrent EOC should guide future trials. Here, we evaluated the TME of paired primary and recurrent tumors (n = 17), and non-paired primary (n = 20) and recurrent (n = 15) tumors, for CD8+ T cells, FOXP3+ regulatory T cells (Tregs), CD68+ tumor-associated macrophages (TAMs), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1). CD8+ T cells were similar in primary and recurrent tumors, but Tregs were higher in recurrent tumors (P =.0210). Higher TAM density (≥5%) associated with higher Tregs (P =.001) and CD8+ T cells (P <.001) in recurrent tumors, but only with higher Tregs in primary tumors (P =.02). TAM-dense recurrent tumors expressed PD-L1 on tumor and immune cells, whereas TAM-dense primary tumors expressed PD-L1 predominantly on immune cells. In survival analyses, higher Tregs in primary tumors correlated with decreased time to first recurrence (17.0 versus 28.5 months, P =.022). Conversely, higher Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met versus 20.0 months, P =.022). TAM density did not affect patient survival. However, patients with increased TAMs at recurrence (n = 5) had longer OS from recurrence compared to patients without increased TAMs (n = 12) (56.0 versus 20.0 months); with the small sample size, this did not reach statistical significance (P =.074). Further characterization of the evolution of the TME is warranted.

KW - CD8+ T cells

KW - Ovarian cancer

KW - PD-1/PD-L1

KW - Regulatory T cells

KW - Tumor-associated macrophages

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