TGF-β1 programmed myeloid-derived suppressor cells (MDSC) acquire immune-stimulating and tumor killing activity capable of rejecting established tumors in combination with radiotherapy

Padmini Jayaraman, Falguni Parikh, Jared M. Newton, Aurelie Hanoteau, Charlotte Rivas, Rosemarie Krupar, Kimal Rajapakshe, Ravi Pathak, Kavin Kanthaswamy, Cassie MacLaren, Shixia Huang, Cristian Coarfa, Chad Spanos, Dean P. Edwards, Robin Parihar, Andrew G. Sikora

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Cancer-induced myeloid-derived suppressor cells (MDSC) play an important role in tumor immune evasion. MDSC programming or polarization has been proposed as a strategy for leveraging the developmental plasticity of myeloid cells to reverse MDSC immune suppressive functions, or cause them to acquire anti-tumor activity. While MDSC derived ex vivo from murine bone marrow precursor cells with tumor-conditioned medium efficiently suppressed T cell proliferation, MDSC derived from conditioned medium in presence of TGF-β1 (TGFβ-MDSC) acquired a novel immune-stimulatory phenotype, losing the ability to inhibit T cell proliferation and acquiring enhanced antigen-presenting capability. Altered immune function was associated with SMAD-2 dependent upregulation of maturation and costimulatory molecules, and downregulation of inducible nitric oxide synthase (iNOS), an effector mechanism of immunosuppression. TGFβ-MDSC also upregulated FAS-ligand expression, leading to FAS-dependent killing of murine human papillomavirus (HPV)-associated head and neck cancer cells and tumor spheroids in vitro and anti-tumor activity in vivo. Radiation upregulated FAS expression on tumor cells, and the combination of radiotherapy and intratumoral injection of TGFβ-MDSC strongly enhanced class I expression on tumor cells and induction of HPV E7 tetramer-positive CD8 + T cells, leading to clearance of established tumors and long-term survival. TGFβ-MDSC derived from human PBMC with tumor conditioned medium also lost immunosuppressive function and acquired tumor-killing activity. Thus, TGFβ1 mediated programming of nascent MDSC leads to a potent anti-tumor phenotype potentially suitable for adoptive immunotherapy.

Original languageEnglish
Article numbere1490853
JournalOncoImmunology
Volume7
Issue number10
DOIs
StatePublished - 3 Oct 2018
Externally publishedYes

Keywords

  • CD86
  • MDSC
  • SMAD2
  • TGF-beta
  • adoptive cellular therapy
  • caspase-3
  • myeloid-derived suppressor cells (written out)
  • radiotherapy
  • tumor killing

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