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Regulating the suppressors: apoptosis and inflammation govern the survival of tumor-induced myeloid-derived suppressor cells (MDSC)

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Immune suppressive myeloid-derived suppressor cells (MDSC) are present in most cancer patients where they inhibit innate anti-tumor immunity and are a significant obstacle to cancer immunotherapy. Inflammation is a known inducer of Gr1+CD11b+ MDSC; however, the factors/conditions that regulate MDSC survival and half-life have not been identified. We have used mass spectrometry (MS) and proteomic analysis to identify proteins and pathways that regulate MDSC survival. This analysis revealed high expression of caspase family proteins and the Fas–FasL, p38 MAPK, and TGFβ pathways, suggesting that Fas–FasL apoptosis regulates MDSC survival. Flow cytometry, confocal microscopy, and western blot analyses confirmed the MS findings and demonstrated that Fas+ MDSC are susceptible to Fas-mediated killing in vitro. In vivo studies with FasL-deficient and Fas-deficient mice demonstrated that Fas–FasL interactions are essential for MDSC apoptosis and for rejection of established metastatic disease and survival and that FasL+ T cells are the effector population mediating MDSC apoptosis. MS findings validated by biological experiments demonstrated that inflammation increases MDSC levels by protecting MDSC from Fas-mediated apoptosis, possibly by activating p38 MAPK. These results demonstrate that MDSC half-life in vivo is regulated by FasL+ T cells and that inflammation increases MDSC levels by conferring resistance to Fas-mediated apoptosis and identifies T cells as the relevant effector cells causing MDSC apoptosis in vivo. This newly recognized mechanism for regulating MDSC levels identifies potential new targets for decreasing MDSC in cancer patients.

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Acknowledgments

We thank Dr. Robert Wiltrout for providing breeding stock of BALB/c FasL−/− and Pfp−/− mice. These studies were supported by NIH RO1CA115880 and RO1CA84232 (SOR), and American Cancer Society IRG-97-153-07 (PS). OC was supported by predoctoral fellowship W81XWH-10-10027 from the DOD CDMRP program. CE was partially supported by NIH/NIGMS MARC U*STAR T34 08663 and an HHMI Precollege and Undergraduate Science Education grant. Animal studies described herein were approved by the UMBC Institutional Animal Care and Use Committee.

Conflict of interest

The authors have no conflict of interest with the organizations sponsoring this research.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, 21250, USA

    Suzanne Ostrand-Rosenberg, Pratima Sinha, Olesya Chornoguz & Christopher Ecker

Authors
  1. Suzanne Ostrand-Rosenberg
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  2. Pratima Sinha
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  3. Olesya Chornoguz
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  4. Christopher Ecker
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Corresponding author

Correspondence to Suzanne Ostrand-Rosenberg.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Eleventh International Conference on Progress in Vaccination against Cancer (PIVAC 11), held in Copenhagen, Denmark, 10th–13th October 2011. It is part of a CII series of Focussed Research Reviews and meeting report.

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Ostrand-Rosenberg, S., Sinha, P., Chornoguz, O. et al. Regulating the suppressors: apoptosis and inflammation govern the survival of tumor-induced myeloid-derived suppressor cells (MDSC). Cancer Immunol Immunother 61, 1319–1325 (2012). https://doi.org/10.1007/s00262-012-1269-6

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  • DOI: https://doi.org/10.1007/s00262-012-1269-6

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