2. Academic Validation
  3. Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer

Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer

  • J Immunother Cancer. 2018 Oct 1;6(1):98. doi: 10.1186/s40425-018-0406-y.
Nathan D Pennock 1,  Holly A Martinson 2,  Qiuchen Guo 1,  Courtney B Betts 1,  Sonali Jindal 1,  Takahiro Tsujikawa 3,  Lisa M Coussens 1 4,  Virginia F Borges 5 6,  Pepper Schedin 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 SW Moody Ave, Portland, OR, 97201, USA.
  • 2 WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence Dr, Anchorage, AK, 99508, USA.
  • 3 Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Kyoto Prefecture, Japan.
  • 4 Knight Cancer Institute, Oregon Health & Science University, 2720 SW Moody Ave, Portland, OR, 97201, USA.
  • 5 Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, MS8117, RC-1S, 8401K, 12801 E 17th Ave, Aurora, CO, 80045, USA.
  • 6 Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, 1665 Aurora Court, Aurora, CO, 80045, USA.
  • 7 Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 SW Moody Ave, Portland, OR, 97201, USA. Schedin@ohsu.edu.
  • 8 Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, MS8117, RC-1S, 8401K, 12801 E 17th Ave, Aurora, CO, 80045, USA. Schedin@ohsu.edu.
  • 9 Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, 1665 Aurora Court, Aurora, CO, 80045, USA. Schedin@ohsu.edu.
  • 10 Knight Cancer Institute, Oregon Health & Science University, 2720 SW Moody Ave, Portland, OR, 97201, USA. Schedin@ohsu.edu.
PMID: 30285905 DOI: 10.1186/s40425-018-0406-y
Abstract

Background: Women diagnosed with breast Cancer within 5 years postpartum (PPBC) have poorer prognosis than age matched nulliparous women, even after controlling for clinical variables known to impact disease outcomes. Through rodent modeling, the poor prognosis of PPBC has been attributed to physiologic mammary gland involution, which shapes a tumor promotional microenvironment through induction of wound-healing-like programs including myeloid cell recruitment. Previous studies utilizing immune compromised mice have shown that blocking prostaglandin synthesis reduces PPBC tumor progression in a tumor cell extrinsic manner. Given the reported roles of prostaglandins in myeloid and T Cell Biology, and the established importance of these immune cell populations in dictating tumor growth, we investigate the impact of involution on shaping the tumor immune milieu and its mitigation by ibuprofen in immune competent hosts.

Methods: In a syngeneic (D2A1) orthotopic Balb/c mouse model of PPBC, we characterized the impact of mammary gland involution and ibuprofen treatment on the immune milieu in tumors and draining lymph nodes utilizing flow cytometry, multiplex IHC, lipid mass spectroscopy and cytokine arrays. To further investigate the impact of ibuprofen on programming myeloid cell populations, we performed RNA-Seq on in vivo derived mammary myeloid cells from ibuprofen treated and untreated involution group mice. Further, we examined direct effects of ibuprofen through in vitro bone marrow derived myeloid cell cultures.

Results: Tumors implanted into the mammary involution microenvironment grow more rapidly and display a distinct immune milieu compared to tumors implanted into glands of nulliparous mice. This milieu is characterized by increased presence of immature monocytes and reduced numbers of T cells and is reversed upon ibuprofen treatment. Further, ibuprofen treatment enhances Th1 associated cytokines as well as promotes tumor border accumulation of T cells. Safety studies demonstrate ibuprofen does not impede gland involution, impact subsequent reproductive success, nor promote auto-reactivity as detected through auto-antibody and naïve T cell priming assays.

Conclusions: Ibuprofen administration during the tumor promotional microenvironment of the involuting mammary gland reduces overall tumor growth and enhances anti-tumor immune characteristics while avoiding adverse autoimmune reactions. In sum, these studies implicate beneficial prophylactic use of ibuprofen during the pro-tumorigenic window of mammary gland involution.

Keywords

Ibuprofen; Macrophages; Multiplex IHC; NSAIDs; Postpartum breast cancer; T cells; Tumor microenvironment.

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