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Programming of MDSC: New Opportunities for Targeted Therapy

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The Tumor Immunoenvironment

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Abstract

Myeloid-derived suppressor cells have recently been widely recognized as major players in tumor-mediated immunosuppression. MDSCs act to suppress antitumor immunity through increased production of Arginase, Reactive Oxygen Species (ROS), up regulation of inducible Nitric Oxide Synthase (iNOS), and expression of negative costimulatory molecules, leading to inhibition of both antigen-specific and bystander T cell responses. These immature myeloid precursors are recruited peripherally and to tumors by inflammation, which retards their differentiation into mature myeloid lineages. MDSCs can be subdivided into Granulocytic (G-MDSC) and Monocytic (M-MDSC) forms. Both lineages can further differentiate into phenotypic forms analogous to those previously described in macrophages and neutrophils, including a so-called Type 1 and Type 2 phenotypes, which are functionally tumoricidal or promote tumor growth and progression, respectively. While eliminating MDSCs or inducing their differentiation into conventional myeloid lineages are potential strategies to restore anti-tumor immunity, the existence of opposing functional phenotypes presents an opportunity to drive MDSC towards Type 1 polarization to reverse tumor-mediated immunosuppression. Interference with the PIR (paired immunoglobulin like receptor) pathway and TGF-β receptor signaling has been shown to cause such a reorientation of M-MDSCs and G-MDSCs in murine models. Exploitation of this principle in humans, including the use of small molecule inhibitors and biological therapies which alter the balance of Type 1 and Type 2 polarization may lead to novel therapeutic approaches, particularly, in combination with existing immunomodulatory strategies focused on enhancing antitumor T cell responses (such as vaccination and immune checkpoint blockade).

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Authors and Affiliations

  1. Department of Oncological Sciences, Surgery, Immunology Institute and Tisch Cancer Institute, Mount Sinai School of Medicine, Icahn Medical Institute, Room 13 70C 1425 Madison Avenue, NY, 10029, USA

    Shu-Hsia Chen

  2. Department of Otolaryngology, Dermatology, Immunology Institute, Tisch Cancer Institute, Mount Sinai School of Medicine, Icahn Medical Institute, 1425 Madison Avenue, NY, 10029, USA

    Peter Svider & Andrew G. Sikora

  3. Department of Oncological Sciences,and Immunology Institute, Mount Sinai School of Medicine, Icahn Medical Institute, 1425 Madison Avenue, NY, 10029, USA

    Wen-Chin Yang

  4. Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan, China

    Wen-Chin Yang

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  1. Peter Svider
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  2. Shu-Hsia Chen
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  3. Andrew G. Sikora
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  4. Wen-Chin Yang
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Correspondence to Shu-Hsia Chen or Andrew G. Sikora .

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Editors and Affiliations

  1. Department of Pathology, University of Pittsburgh Medical Center, 3550 Terrace Street Scaife Hal, Pittsburgh, 15213, Pennsylvania, USA

    Michael R. Shurin

  2. , Clinical Cooperation Unit Dermato-Oncolo, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    Viktor Umansky

  3. , SAIC-Frederick, Inc., National Cancer Institute at Frederick, Post Office B, Frederick, 21702, Maryland, USA

    Anatoli Malyguine

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Svider, P., Chen, SH., Sikora, A.G., Yang, WC. (2013). Programming of MDSC: New Opportunities for Targeted Therapy. In: Shurin, M., Umansky, V., Malyguine, A. (eds) The Tumor Immunoenvironment. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6217-6_24

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