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Sarhan D, Leijonhufvud C, Murray S, et al. Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer. Oncoimmunology. 2017;6(8):e1338238doi: 10.1080/2162402X.2017.1338238.
Sarhan, D., Leijonhufvud, C., Murray, S., Witt, K., Seitz, C., Wallerius, M., Xie, H., Ullén, A., Harmenberg, U., Lidbrink, E., Rolny, C., Andersson, J., & Lundqvist, A. (2017). Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer. Oncoimmunology, 6(8), e1338238. https://doi.org/10.1080/2162402X.2017.1338238
Sarhan, Dhifaf, et al. "Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer." Oncoimmunology vol. 6,8 (2017): e1338238. doi: https://doi.org/10.1080/2162402X.2017.1338238
Sarhan D, Leijonhufvud C, Murray S, Witt K, Seitz C, Wallerius M, Xie H, Ullén A, Harmenberg U, Lidbrink E, Rolny C, Andersson J, Lundqvist A. Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer. Oncoimmunology. 2017 Jun 14;6(8):e1338238. doi: 10.1080/2162402X.2017.1338238. eCollection 2017. PMID: 28920001; PMCID: PMC5593706.
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Oncoimmunology. 2017 Jun 14;6(8):e1338238. doi: 10.1080/2162402X.2017.1338238. eCollection 2017.

Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer.

Oncoimmunology

Dhifaf Sarhan, Caroline Leijonhufvud, Shannon Murray, Kristina Witt, Christina Seitz, Majken Wallerius, Hanjing Xie, Anders Ullén, Ulrika Harmenberg, Elisabet Lidbrink, Charlotte Rolny, John Andersson, Andreas Lundqvist

Affiliations

  1. Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  2. University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA.
  3. Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  4. Cell Therapy Institute, Nova Southeastern University, FL, USA.
  5. Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  6. Department of Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
  7. Division of Radiotherapy, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.

PMID: 28920001 PMCID: PMC5593706 DOI: 10.1080/2162402X.2017.1338238

Abstract

Regulatory T cells (Treg) suppress anti-tumor immune responses and their infiltration in the tumor microenvironment is associated with inferior prognosis in cancer patients. Thus, in order to enhance anti-tumor immune responses, selective depletion of Treg is highly desired. We found that treatment with zoledronic acid (ZA) resulted in a selective decrease in the frequency of Treg that was associated with a significant increase in proliferation of T cells and natural killer (NK) cells in peripheral blood of patients with metastatic cancer. In vitro, genome-wide transcriptomic analysis revealed alterations in calcium signaling pathways in Treg following treatment with ZA. Furthermore, co-localization of the nuclear factor of activated T cells (NFAT) and forkhead box P3 (FOXP3) was significantly reduced in Treg upon ZA-treatment. Consequently, reduced expression levels of CD25, STAT5 and TGFβ were observed. Functionally, ZA-treated Treg had reduced capacity to suppress T and NK cell proliferation and anti-tumor responses compared with untreated Treg in vitro. Treatment with ZA to selectively inhibit essential signaling pathways in Treg resulting in reduced capacity to suppress effector T and NK cell responses represents a novel approach to inhibit Treg activity in patients with cancer.

Keywords: Ca2+/calcineurin/NFAT pathway; NK and T cell function; Zoledronic acid; cancer patients; regulatory T cells

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