Mannose Receptor–positive Macrophage Infiltration Correlates with Prostate Cancer Onset and Metastatic Castration-resistant Disease

Jelani Zarif, Javier A. Baena-Del Valle, Jessica L. Hicks, Christopher M Heaphy, Igor Vidal, Jacob Luo, Tamara Lotan, Jody Hooper, William B Isaacs, Kenneth Pienta, Angelo Michael Demarzo

Research output: Contribution to journalArticle

Abstract

Background: M2 tumor-associated macrophages (M2-TAMs) can suppress inflammation in the tumor microenvironment and have been reported to modulate cancer progression. We and others have previously reported M2-TAM infiltration in metastatic castration-resistant prostate cancer (mCRPC). Objective: To determine whether the extent of M2-TAM infiltration correlates with PC aggressiveness. Design, setting, and participants: Normal prostate tissue, localized PC, and mCRPC samples from 192 patients were retrospectively analyzed. Outcome measurements and statistical analysis: We analytically validated an immunohistochemistry assay for detection of the human mannose receptor (CD206) to assess M2 macrophage involvement. Results and limitations: Multiplex immunofluorescent staining showed that a small fraction of CD206 staining co-localized with the endothelial cells of lymphatic vessels, while the vast majority of staining occurred in CD68-positive macrophages. The area fraction of staining for CD206-positive macrophages increased in a stepwise fashion from normal (ie, no inflammation) prostate tissue, to primary untreated carcinomas, to hormone-naïve regional lymph node metastases, to mCRPC. Complementary studies using flow cytometry confirmed CD206-positive M2-TAM infiltration. Limitations include the small number of rapid autopsy samples and the lack of neuroendocrine PC samples. Conclusions: Our results revealed a progressive increase in CD206-positive macrophages from normal prostate to mCRPC. Given the immunosuppressive nature of macrophages and the lack of clinical success of immunotherapy for PC patients, our results provide a rationale for therapeutic targeting of macrophages in the PC microenvironment as a potential method to augment immunotherapeutic responses. Patient summary: In this report we used 192 prostate cancer samples to determine if M2 macrophage infiltration is correlated with castration resistance in prostate cancer.

Original languageEnglish (US)
Pages (from-to)429-436
Number of pages8
JournalEuropean Urology Oncology
Volume2
Issue number4
DOIs
StatePublished - Jul 1 2019

Fingerprint

Castration
Mannose
Prostatic Neoplasms
Macrophages
Staining and Labeling
Prostate
Inflammation
Lymphatic Vessels
Tumor Microenvironment
Immunosuppressive Agents
Immunotherapy
Autopsy
Neoplasms
Flow Cytometry
Endothelial Cells
Lymph Nodes
Immunohistochemistry
Hormones
Neoplasm Metastasis
Carcinoma

Keywords

  • Castration-resistant prostate cancer
  • M2 tumor-associated macrophages
  • Mannose receptor
  • Prostate cancer

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Surgery
  • Oncology
  • Urology

Cite this

@article{43b3ef73fcee427798b8ff125ad717a5,
title = "Mannose Receptor–positive Macrophage Infiltration Correlates with Prostate Cancer Onset and Metastatic Castration-resistant Disease",
abstract = "Background: M2 tumor-associated macrophages (M2-TAMs) can suppress inflammation in the tumor microenvironment and have been reported to modulate cancer progression. We and others have previously reported M2-TAM infiltration in metastatic castration-resistant prostate cancer (mCRPC). Objective: To determine whether the extent of M2-TAM infiltration correlates with PC aggressiveness. Design, setting, and participants: Normal prostate tissue, localized PC, and mCRPC samples from 192 patients were retrospectively analyzed. Outcome measurements and statistical analysis: We analytically validated an immunohistochemistry assay for detection of the human mannose receptor (CD206) to assess M2 macrophage involvement. Results and limitations: Multiplex immunofluorescent staining showed that a small fraction of CD206 staining co-localized with the endothelial cells of lymphatic vessels, while the vast majority of staining occurred in CD68-positive macrophages. The area fraction of staining for CD206-positive macrophages increased in a stepwise fashion from normal (ie, no inflammation) prostate tissue, to primary untreated carcinomas, to hormone-na{\"i}ve regional lymph node metastases, to mCRPC. Complementary studies using flow cytometry confirmed CD206-positive M2-TAM infiltration. Limitations include the small number of rapid autopsy samples and the lack of neuroendocrine PC samples. Conclusions: Our results revealed a progressive increase in CD206-positive macrophages from normal prostate to mCRPC. Given the immunosuppressive nature of macrophages and the lack of clinical success of immunotherapy for PC patients, our results provide a rationale for therapeutic targeting of macrophages in the PC microenvironment as a potential method to augment immunotherapeutic responses. Patient summary: In this report we used 192 prostate cancer samples to determine if M2 macrophage infiltration is correlated with castration resistance in prostate cancer.",
keywords = "Castration-resistant prostate cancer, M2 tumor-associated macrophages, Mannose receptor, Prostate cancer",
author = "Jelani Zarif and {Baena-Del Valle}, {Javier A.} and Hicks, {Jessica L.} and Heaphy, {Christopher M} and Igor Vidal and Jacob Luo and Tamara Lotan and Jody Hooper and Isaacs, {William B} and Kenneth Pienta and Demarzo, {Angelo Michael}",
year = "2019",
month = "7",
day = "1",
doi = "10.1016/j.euo.2018.09.014",
language = "English (US)",
volume = "2",
pages = "429--436",
journal = "European urology oncology",
issn = "2588-9311",
publisher = "Elsevier BV",
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TY - JOUR

T1 - Mannose Receptor–positive Macrophage Infiltration Correlates with Prostate Cancer Onset and Metastatic Castration-resistant Disease

AU - Zarif, Jelani

AU - Baena-Del Valle, Javier A.

AU - Hicks, Jessica L.

AU - Heaphy, Christopher M

AU - Vidal, Igor

AU - Luo, Jacob

AU - Lotan, Tamara

AU - Hooper, Jody

AU - Isaacs, William B

AU - Pienta, Kenneth

AU - Demarzo, Angelo Michael

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background: M2 tumor-associated macrophages (M2-TAMs) can suppress inflammation in the tumor microenvironment and have been reported to modulate cancer progression. We and others have previously reported M2-TAM infiltration in metastatic castration-resistant prostate cancer (mCRPC). Objective: To determine whether the extent of M2-TAM infiltration correlates with PC aggressiveness. Design, setting, and participants: Normal prostate tissue, localized PC, and mCRPC samples from 192 patients were retrospectively analyzed. Outcome measurements and statistical analysis: We analytically validated an immunohistochemistry assay for detection of the human mannose receptor (CD206) to assess M2 macrophage involvement. Results and limitations: Multiplex immunofluorescent staining showed that a small fraction of CD206 staining co-localized with the endothelial cells of lymphatic vessels, while the vast majority of staining occurred in CD68-positive macrophages. The area fraction of staining for CD206-positive macrophages increased in a stepwise fashion from normal (ie, no inflammation) prostate tissue, to primary untreated carcinomas, to hormone-naïve regional lymph node metastases, to mCRPC. Complementary studies using flow cytometry confirmed CD206-positive M2-TAM infiltration. Limitations include the small number of rapid autopsy samples and the lack of neuroendocrine PC samples. Conclusions: Our results revealed a progressive increase in CD206-positive macrophages from normal prostate to mCRPC. Given the immunosuppressive nature of macrophages and the lack of clinical success of immunotherapy for PC patients, our results provide a rationale for therapeutic targeting of macrophages in the PC microenvironment as a potential method to augment immunotherapeutic responses. Patient summary: In this report we used 192 prostate cancer samples to determine if M2 macrophage infiltration is correlated with castration resistance in prostate cancer.

AB - Background: M2 tumor-associated macrophages (M2-TAMs) can suppress inflammation in the tumor microenvironment and have been reported to modulate cancer progression. We and others have previously reported M2-TAM infiltration in metastatic castration-resistant prostate cancer (mCRPC). Objective: To determine whether the extent of M2-TAM infiltration correlates with PC aggressiveness. Design, setting, and participants: Normal prostate tissue, localized PC, and mCRPC samples from 192 patients were retrospectively analyzed. Outcome measurements and statistical analysis: We analytically validated an immunohistochemistry assay for detection of the human mannose receptor (CD206) to assess M2 macrophage involvement. Results and limitations: Multiplex immunofluorescent staining showed that a small fraction of CD206 staining co-localized with the endothelial cells of lymphatic vessels, while the vast majority of staining occurred in CD68-positive macrophages. The area fraction of staining for CD206-positive macrophages increased in a stepwise fashion from normal (ie, no inflammation) prostate tissue, to primary untreated carcinomas, to hormone-naïve regional lymph node metastases, to mCRPC. Complementary studies using flow cytometry confirmed CD206-positive M2-TAM infiltration. Limitations include the small number of rapid autopsy samples and the lack of neuroendocrine PC samples. Conclusions: Our results revealed a progressive increase in CD206-positive macrophages from normal prostate to mCRPC. Given the immunosuppressive nature of macrophages and the lack of clinical success of immunotherapy for PC patients, our results provide a rationale for therapeutic targeting of macrophages in the PC microenvironment as a potential method to augment immunotherapeutic responses. Patient summary: In this report we used 192 prostate cancer samples to determine if M2 macrophage infiltration is correlated with castration resistance in prostate cancer.

KW - Castration-resistant prostate cancer

KW - M2 tumor-associated macrophages

KW - Mannose receptor

KW - Prostate cancer

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U2 - 10.1016/j.euo.2018.09.014

DO - 10.1016/j.euo.2018.09.014

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JO - European urology oncology

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