Immune cell analyses of the tumor microenvironment in prostate cancer highlight infiltrating regulatory T cells and macrophages as adverse prognostic factors

Line B Andersen; Maibritt Nørgaard; Martin Rasmussen; Jacob Fredsøe; Michael Borre; Benedicte P Ulhøi; Karina D Sørensen

doi:10.1002/path.5757

Immune cell analyses of the tumor microenvironment in prostate cancer highlight infiltrating regulatory T cells and macrophages as adverse prognostic factors

J Pathol. 2021 Oct;255(2):155-165. doi: 10.1002/path.5757. Epub 2021 Aug 10.

Authors

Line B Andersen^{1

2}, Maibritt Nørgaard^{1

2}, Martin Rasmussen^{1

2}, Jacob Fredsøe^{1

2}, Michael Borre^{2

3}, Benedicte P Ulhøi^{2

4}, Karina D Sørensen^{1

2}

Affiliations

¹ Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
² Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
³ Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
⁴ Department of Pathology, Aarhus University Hospital, Aarhus, Denmark.

PMID: 34255349
DOI: 10.1002/path.5757

Abstract

Improved risk stratification is needed for patients with localized prostate cancer. This study characterized and assessed the prognostic potential of distinct immune cell infiltration patterns in the prostate tumor microenvironment. Using tissue microarrays, multiplex immunohistochemistry/immunofluorescence, and automated digital pathology, we analyzed radical prostatectomy specimens from two large patient cohorts (training: n = 470; validation: n = 333) to determine infiltration levels of seven immune cell types in malignant versus benign prostate tissue: CD3⁺ CD8^- FoxP3^- T helper cells, CD3⁺ CD8⁺ FoxP3^- cytotoxic T cells (CTLs), CD3⁺ CD8^- FoxP3⁺ regulatory T cells (T_regs ), CD20⁺ B cells, CD68⁺ CD163^- M1 macrophages, CD68⁺ CD163⁺ M2 macrophages, and tryptase⁺ mast cells. Results were further validated by cell type enrichment analyses of bulk tumor RNAseq data from a third independent patient cohort (n = 99). Prognostic potential was assessed by Kaplan-Meier and uni-/multi-variate Cox regression analyses. Clinical endpoint was biochemical recurrence. All seven immune cell types were enriched in prostate cancer versus benign stroma, while there was selective enrichment for B cells, T_regs , M1 and M2 macrophages, and depletion of mast cells and CTLs in prostate cancer epithelium. In all three cohorts, high levels of infiltrating T_regs , M1, and M2 macrophages in stroma and/or epithelium were associated with biochemical recurrence (p < 0.05; log-rank test). After adjustment for routine clinical variables, T_regs and M2 macrophages remained significant adverse predictors of biochemical recurrence (p < 0.05; multivariate Cox regression). Our comprehensive analyses of immune cell infiltration patterns in the prostate tumor microenvironment highlight infiltrating T_regs , M1, and M2 macrophages as adverse predictors of prostate cancer outcome. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: RNA sequencing; biomarker; digital pathology; immune cells; prostate cancer; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Humans
Lymphocytes, Tumor-Infiltrating / immunology*
Male
Middle Aged
Prognosis
Prostatic Neoplasms / immunology*
Prostatic Neoplasms / pathology
T-Lymphocytes, Regulatory / immunology*
Tumor Microenvironment / immunology*
Tumor-Associated Macrophages / immunology*