Skip to main content
SpringerLink
Log in

Role and Therapeutic Implications of MDSCs in Sarcomas

  • Chapter
  • First Online:
Immunotherapy of Sarcoma

  • 491 Accesses

Abstract

Understanding the interplay of the positive and negative regulators of the immune system in sarcomagenesis will be crucial to identifying approaches to use immunotherapies for this rare and heterogeneous group of diseases. In this chapter, we explore the known role of myeloid-derived suppressor cells (MDSCs) in creating an immunosuppressive state in the tumor microenvironment. We highlight current issues with properly defining this heterogeneous continuum of cells with apparent context dependent phenotypic plasticity. Some of the known direct and indirect effects of MDSCs on immune effector cells are explored and several strategies aimed at inhibiting this immunosuppressive cellular compartment in model systems are examined. Further research is required to better characterize and understand the function of MDSCs and to study them in the human condition.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 99.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Youn JI, Gabrilovich DI. The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol. 2010;40:2969–75.

    Article  CAS  Google Scholar 

  2. Ugel S, De Sanctis F, Mandruzzato S, Bronte V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest. 2015;125:3365–76.

    Article  Google Scholar 

  3. Wesolowski R, Markowitz J, Carson WE. Myeloid derived suppressor cells - a new therapeutic target in the treatment of cancer. J Immunother Cancer. 2013;1:10.

    Article  Google Scholar 

  4. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    Article  CAS  Google Scholar 

  5. Solito S, et al. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 2014;1319:47–65.

    Article  CAS  Google Scholar 

  6. Highfill SL, et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. 2014;6:237ra267.

    Article  Google Scholar 

  7. Llitjos JF, et al. Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4. J Pathol. 2016;239:473–83.

    Article  CAS  Google Scholar 

  8. Adah D, et al. Implications of MDSCs-targeting in lung cancer chemo-immunotherapeutics. Pharmacol Res. 2016;110:25–34.

    Article  CAS  Google Scholar 

  9. Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res. 2015;128:95–139.

    Article  Google Scholar 

  10. Wang Z, Liu Y, Zhang Y, Shang Y, Gao Q. MDSC-decreasing chemotherapy increases the efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma and pancreatic cancer. Oncotarget. 2016;7:4760–9.

    PubMed  Google Scholar 

  11. Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nat Rev Cancer. 2016;16:447–62.

    Article  CAS  Google Scholar 

  12. Duncan BB, et al. A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy. J Immunother. 2013;36:400–11.

    Article  CAS  Google Scholar 

  13. Zhang H, et al. Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood. 2013;122:1105–13.

    Article  CAS  Google Scholar 

  14. Zoso A, et al. Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion. Eur J Immunol. 2014;44:3307–19.

    Article  CAS  Google Scholar 

  15. Vanderstraeten A, Luyten C, Verbist G, Tuyaerts S, Amant F. Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy. Cancer Immunol Immunother. 2014;63:545–57.

    Article  CAS  Google Scholar 

  16. Tazzari M, et al. Adaptive immune contexture at the tumour site and downmodulation of circulating myeloid-derived suppressor cells in the response of solitary fibrous tumour patients to anti-angiogenic therapy. Br J Cancer. 2014;111:1350–62.

    Article  CAS  Google Scholar 

  17. Finkelstein SE, et al. Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. Int J Radiat Oncol Biol Phys. 2012;82:924–32.

    Article  Google Scholar 

  18. Hao Z, Sadek I. Sunitinib: the antiangiogenic effects and beyond. Onco Targets Ther. 2016;9:5495–505.

    Article  CAS  Google Scholar 

  19. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol. 2004;172:989–99.

    Article  CAS  Google Scholar 

  20. Schmielau J, Finn OJ. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res. 2001;61:4756–60.

    CAS  PubMed  Google Scholar 

  21. Nagaraj S, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med. 2007;13:828–35.

    Article  CAS  Google Scholar 

  22. Sinha P, Clements VK, Ostrand-Rosenberg S. Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol. 2005;174:636–45.

    Article  CAS  Google Scholar 

  23. Motoshima T, et al. Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells. Oncol Rep. 2015;33:2947–53.

    Article  CAS  Google Scholar 

  24. Huang B, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 2006;66:1123–31.

    Article  CAS  Google Scholar 

  25. Yang R, et al. CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells. Cancer Res. 2006;66:6807–15.

    Article  CAS  Google Scholar 

  26. Movahedi K, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood. 2008;111:4233–44.

    Article  CAS  Google Scholar 

  27. Long AH, et al. Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol Res. 2016;4:869–80.

    Article  CAS  Google Scholar 

  28. Tsukamoto H, Nishikata R, Senju S, Nishimura Y. Myeloid-derived suppressor cells attenuate TH1 development through IL-6 production to promote tumor progression. Cancer Immunol Res. 2013;1:64–76.

    Article  CAS  Google Scholar 

  29. Cheng P, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med. 2008;205:2235–49.

    Article  CAS  Google Scholar 

  30. Cohen PA, et al. Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape. Immunol Investig. 2012;41:680–710.

    Article  CAS  Google Scholar 

  31. Geiger R, et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829.e813–42.e813.

    Article  Google Scholar 

  32. Balachandran VP, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17:1094–100.

    Article  CAS  Google Scholar 

  33. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707–23.

    Article  CAS  Google Scholar 

  34. Germano G, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013;23:249–62.

    Article  CAS  Google Scholar 

  35. Germano G, et al. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res. 2010;70:2235–44.

    Article  CAS  Google Scholar 

  36. Rao A, et al. Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells. Cancer Res. 2012;72:3196–206.

    Article  CAS  Google Scholar 

  37. Qu Y, et al. Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment. J Immunol. 2010;185:2895–902.

    Article  CAS  Google Scholar 

  38. Garton AJ, et al. Anti-KIT monoclonal antibody treatment enhances the antitumor activity of immune checkpoint inhibitors by reversing tumor-induced immunosuppression. Mol Cancer Ther. 2017;16:671–80.

    Article  CAS  Google Scholar 

  39. D’Angelo SP, et al. Combined KIT and CTLA-4 blockade in patients with refractory GIST and other advanced sarcomas: a phase Ib study of dasatinib plus ipilimumab. Clin Cancer Res. 2017;23:2972–80.

    Article  Google Scholar 

  40. Fernandez A, et al. Inhibition of tumor-induced myeloid-derived suppressor cell function by a nanoparticulated adjuvant. J Immunol. 2011;186:264–74.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, University of California, Los Angeles, Santa Monica, CA, USA

    Brittany Lala & Arun S. Singh

  2. Department of Radiation Oncology, University of California, Los Angeles, Santa Monica, CA, USA

    Anusha Kalbasi

Authors
  1. Brittany Lala
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anusha Kalbasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arun S. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arun S. Singh .

Editor information

Editors and Affiliations

  1. Department of Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, USA

    Sandra P. D'Angelo

  2. Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA

    Seth M. Pollack

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lala, B., Kalbasi, A., Singh, A.S. (2019). Role and Therapeutic Implications of MDSCs in Sarcomas. In: D'Angelo, S., Pollack, S. (eds) Immunotherapy of Sarcoma. Springer, Cham. https://doi.org/10.1007/978-3-319-93530-0_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-93530-0_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-93529-4

  • Online ISBN: 978-3-319-93530-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation