DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer

Meghan Travers, Stephen M. Brown, Matthew Dunworth, Cassandra E. Holbert, Karla R. Wiehagen, Kurtis E. Bachman, Jackson R. Foley, Meredith L. Stone, Stephen B Baylin, Robert A Casero, Cynthia Zahnow

Research output: Contribution to journalArticle

Abstract

Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumormicroenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome. We tested this hypothesis in an immunocompetent mouse model for ovarian cancer and found that in vivo, 5AZA-C and DFMO, either alone or in combination, significantly increased survival, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK cells. The combination therapy had a striking increase in survival when compared with single-agent treatment, despite a smaller difference in recruited lymphocytes. Instead, combination therapy led to a significant decrease in immunosuppressive cells such as M2 polarized macrophages and an increase in tumor-killing M1 macrophages. In this model, depletion of macrophages with a CSF1Rblocking antibody reduced the efficacy of 5AZA-C + DFMO treatment and resulted in fewer M1 macrophages in the tumor microenvironment. These observations suggest our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival.

Original languageEnglish (US)
Pages (from-to)3445-3454
Number of pages10
JournalCancer Research
Volume79
Issue number13
DOIs
StatePublished - Jan 1 2019

Fingerprint

Eflornithine
Azacitidine
Tumor Microenvironment
Ovarian Neoplasms
Macrophages
Immunosuppressive Agents
T-Lymphocytes
Natural Killer Cells
Interferon Type I
Therapeutics
Tumor Burden
Epigenomics
Neoplasms
Lymphocytes
Antibodies
Incidence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Travers, M., Brown, S. M., Dunworth, M., Holbert, C. E., Wiehagen, K. R., Bachman, K. E., ... Zahnow, C. (2019). DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer. Cancer Research, 79(13), 3445-3454. https://doi.org/10.1158/0008-5472.CAN-18-4018

DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer. / Travers, Meghan; Brown, Stephen M.; Dunworth, Matthew; Holbert, Cassandra E.; Wiehagen, Karla R.; Bachman, Kurtis E.; Foley, Jackson R.; Stone, Meredith L.; Baylin, Stephen B; Casero, Robert A; Zahnow, Cynthia.

In: Cancer Research, Vol. 79, No. 13, 01.01.2019, p. 3445-3454.

Research output: Contribution to journalArticle

Travers, M, Brown, SM, Dunworth, M, Holbert, CE, Wiehagen, KR, Bachman, KE, Foley, JR, Stone, ML, Baylin, SB, Casero, RA & Zahnow, C 2019, 'DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer', Cancer Research, vol. 79, no. 13, pp. 3445-3454. https://doi.org/10.1158/0008-5472.CAN-18-4018
Travers M, Brown SM, Dunworth M, Holbert CE, Wiehagen KR, Bachman KE et al. DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer. Cancer Research. 2019 Jan 1;79(13):3445-3454. https://doi.org/10.1158/0008-5472.CAN-18-4018
Travers, Meghan ; Brown, Stephen M. ; Dunworth, Matthew ; Holbert, Cassandra E. ; Wiehagen, Karla R. ; Bachman, Kurtis E. ; Foley, Jackson R. ; Stone, Meredith L. ; Baylin, Stephen B ; Casero, Robert A ; Zahnow, Cynthia. / DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer. In: Cancer Research. 2019 ; Vol. 79, No. 13. pp. 3445-3454.
@article{bda6a73498fb4c729a422cad3c8c1d37,
title = "DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer",
abstract = "Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumormicroenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome. We tested this hypothesis in an immunocompetent mouse model for ovarian cancer and found that in vivo, 5AZA-C and DFMO, either alone or in combination, significantly increased survival, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK cells. The combination therapy had a striking increase in survival when compared with single-agent treatment, despite a smaller difference in recruited lymphocytes. Instead, combination therapy led to a significant decrease in immunosuppressive cells such as M2 polarized macrophages and an increase in tumor-killing M1 macrophages. In this model, depletion of macrophages with a CSF1Rblocking antibody reduced the efficacy of 5AZA-C + DFMO treatment and resulted in fewer M1 macrophages in the tumor microenvironment. These observations suggest our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival.",
author = "Meghan Travers and Brown, {Stephen M.} and Matthew Dunworth and Holbert, {Cassandra E.} and Wiehagen, {Karla R.} and Bachman, {Kurtis E.} and Foley, {Jackson R.} and Stone, {Meredith L.} and Baylin, {Stephen B} and Casero, {Robert A} and Cynthia Zahnow",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/0008-5472.CAN-18-4018",
language = "English (US)",
volume = "79",
pages = "3445--3454",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

TY - JOUR

T1 - DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer

AU - Travers, Meghan

AU - Brown, Stephen M.

AU - Dunworth, Matthew

AU - Holbert, Cassandra E.

AU - Wiehagen, Karla R.

AU - Bachman, Kurtis E.

AU - Foley, Jackson R.

AU - Stone, Meredith L.

AU - Baylin, Stephen B

AU - Casero, Robert A

AU - Zahnow, Cynthia

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumormicroenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome. We tested this hypothesis in an immunocompetent mouse model for ovarian cancer and found that in vivo, 5AZA-C and DFMO, either alone or in combination, significantly increased survival, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK cells. The combination therapy had a striking increase in survival when compared with single-agent treatment, despite a smaller difference in recruited lymphocytes. Instead, combination therapy led to a significant decrease in immunosuppressive cells such as M2 polarized macrophages and an increase in tumor-killing M1 macrophages. In this model, depletion of macrophages with a CSF1Rblocking antibody reduced the efficacy of 5AZA-C + DFMO treatment and resulted in fewer M1 macrophages in the tumor microenvironment. These observations suggest our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival.

AB - Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumormicroenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome. We tested this hypothesis in an immunocompetent mouse model for ovarian cancer and found that in vivo, 5AZA-C and DFMO, either alone or in combination, significantly increased survival, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK cells. The combination therapy had a striking increase in survival when compared with single-agent treatment, despite a smaller difference in recruited lymphocytes. Instead, combination therapy led to a significant decrease in immunosuppressive cells such as M2 polarized macrophages and an increase in tumor-killing M1 macrophages. In this model, depletion of macrophages with a CSF1Rblocking antibody reduced the efficacy of 5AZA-C + DFMO treatment and resulted in fewer M1 macrophages in the tumor microenvironment. These observations suggest our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival.

UR - http://www.scopus.com/inward/record.url?scp=85068821650&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068821650&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-18-4018

DO - 10.1158/0008-5472.CAN-18-4018

M3 - Article

C2 - 31088836

AN - SCOPUS:85068821650

VL - 79

SP - 3445

EP - 3454

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 13

ER -