This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gabrilovich, D. I. Articles by Schreiber, H. Search for Related Content PubMed PubMed Citation Articles by Gabrilovich, D. I. Articles by Schreiber, H.

The Terminology Issue for Myeloid-Derived Suppressor Cells

H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida

Vincenzo Bronte

Istituto Oncologico Veneto, Padova, Italy

Shu-Hsia Chen

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York

Mario P. Colombo

Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy

Augusto Ochoa

Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, New Orleans, Los Angeles

Suzanne Ostrand-Rosenberg

University of Maryland Baltimore County, Baltimore, Maryland

Hans Schreiber

Department of Pathology, The University of Chicago, Chicago, Illinois

To the Editor:

The recent study by Yang et al. (1) described antigen-specific immunosuppression by Gr-1⁺CD11b⁺ myeloid cells, which was mediated by the expression of CD80. This report continued a series of recent articles published in Cancer Research, which provided strong evidence in support of a critical role of these cells in tumor progression (1–6). Recent years have witnessed increasing interest in immunosuppressive cells of myeloid origin. During the last 18 months alone, more than 50 articles have appeared in peer-reviewed journals on this subject. Accumulation of these cells has been reported under pathologic conditions, including bacterial and parasitic infections, acute and chronic inflammation, and traumatic stress. However, most of the attention has been focused on the role of these cells in cancer. Immunosuppressive myeloid cells accumulate in large numbers in tumor-bearing mice, in practically all tested experimental models, as well as in patients with breast, lung, prostate, kidney, head and neck, and other types of cancer. These cells are produced in response to a variety of tumor-derived cytokines and are a heterogeneous mixture of myeloid cells at different stages of differentiation. The precise nature of the suppressor cell population (i.e., precursors of granulocytes, macrophages, dendritic cells, or early myeloid progenitors) depends on the tumor and tumor-derived factors of the hosts. Despite this heterogeneity, immunosuppressive myeloid cells share some common characteristics: lack or reduced expression of markers of mature myeloid cells, expression of both Gr-1 and CD11b molecules in mice, inability to differentiate into mature myeloid cells in the presence of tumor-derived factors, high levels of reactive oxygen species, and activation of arginase I and other molecules. Most importantly, these cells possess a high potential to suppress immune responses in vitro and in vivo. Immunosuppressive myeloid cells are now considered by many as a critical mechanism of tumor escape as well as an important immunosuppressive factor for other pathologic conditions.

Because these cells play a key role in regulation of immunity, we feel it necessary to address one issue that causes confusion in this field. These cells lack a clear, unified name. In the literature, these cells have been called "immature myeloid cells" or "myeloid suppressor cells" (MSC). Although both of these names reflect the biology of cells, neither term is entirely accurate. The name "immature myeloid cells" implies that these cells are normal myeloid precursors. However, this may not be the case. Recent studies have shown clear differences in the biology of normal immature myeloid cells and the cells that accumulate in tumor-bearing hosts. In addition, this term does not reflect the most important feature of these cells: their ability to suppress immune responses. The name "MSC" implies that these cells include populations of mature myeloid cells, such as macrophages or dendritic cells, capable of displaying some immunosuppressive features under certain circumstances. However, this name is also not accurate, being too generic and potentially misleading because these cells are not mature myeloid cells. In addition, the abbreviation "MSC" is commonly used for the characterization of mesenchymal stem cells. We believe that the lack of an accurate name for these cells creates confusion and hampers attempts to develop a cohesive picture of the mechanisms of immunosuppression in cancer and other pathologic conditions.

Therefore, we suggest that these cells be called "myeloid-derived suppressor cells". We believe that this term more closely reflects the origin and function of these cells and hope that it will stimulate further scientific discussions and progress not only in immunology but also in cancer biology where undoubtedly the same or similar cell populations play a major functional role.

References

1. Yang R, Cai Z, Zhang Y, Yutzy WHt, Roby KF, Roden RB. CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1⁺CD11b⁺ myeloid cells. Cancer Res 2006;66:6807–15.[Abstract/Free Full Text]
2. Huang B, Pan PY, Li Q, 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.[Abstract/Free Full Text]
3. Zea AH, Rodriguez PC, Atkins MB, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 2005;65:3044–8.[Abstract/Free Full Text]
4. Nefedova Y, Nagaraj S, Rosenbauer A, Muro-Cacho C, Sebti SM, Gabrilovich DI. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res 2005;65:9525–35.[Abstract/Free Full Text]
5. Mirza N, Fishman M, Fricke I, et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 2006;66:9299–307.[Abstract/Free Full Text]
6. Sinha P, Clements VK, Ostrand-Rosenberg S. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res 2005;65:11743–51.[Abstract/Free Full Text]

This article has been cited by other articles:

				E. M. Hanson, V. K. Clements, P. Sinha, D. Ilkovitch, and S. Ostrand-Rosenberg Myeloid-Derived Suppressor Cells Down-Regulate L-Selectin Expression on CD4+ and CD8+ T Cells J. Immunol., July 15, 2009; 183(2): 937 - 944. [Abstract] [Full Text] [PDF]

				T. J. Stewart, D. J. Liewehr, S. M. Steinberg, K. M. Greeneltch, and S. I. Abrams Modulating the Expression of IFN Regulatory Factor 8 Alters the Protumorigenic Behavior of CD11b+Gr-1+ Myeloid Cells J. Immunol., July 1, 2009; 183(1): 117 - 128. [Abstract] [Full Text] [PDF]

				L. A. Norian, P. C. Rodriguez, L. A. O'Mara, J. Zabaleta, A. C. Ochoa, M. Cella, and P. M. Allen Tumor-Infiltrating Regulatory Dendritic Cells Inhibit CD8+ T Cell Function via L-Arginine Metabolism Cancer Res., April 1, 2009; 69(7): 3086 - 3094. [Abstract] [Full Text] [PDF]

				P. C. Rodriguez, M. S. Ernstoff, C. Hernandez, M. Atkins, J. Zabaleta, R. Sierra, and A. C. Ochoa Arginase I-Producing Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma Are a Subpopulation of Activated Granulocytes Cancer Res., February 15, 2009; 69(4): 1553 - 1560. [Abstract] [Full Text] [PDF]

				K. A. Pilones, N. Kawashima, A. M. Yang, J. S. Babb, S. C. Formenti, and S. Demaria Invariant Natural Killer T Cells Regulate Breast Cancer Response to Radiation and CTLA-4 Blockade Clin. Cancer Res., January 15, 2009; 15(2): 597 - 606. [Abstract] [Full Text] [PDF]

				N. Nausch, I. E. Galani, E. Schlecker, and A. Cerwenka Mononuclear myeloid-derived "suppressor" cells express RAE-1 and activate natural killer cells Blood, November 15, 2008; 112(10): 4080 - 4089. [Abstract] [Full Text] [PDF]

				Z. Li, J. Jiang, Z. Wang, J. Zhang, M. Xiao, C. Wang, Y. Lu, and Z. Qin Endogenous Interleukin-4 Promotes Tumor Development by Increasing Tumor Cell Resistance to Apoptosis Cancer Res., November 1, 2008; 68(21): 8687 - 8694. [Abstract] [Full Text] [PDF]

				P. Sinha, C. Okoro, D. Foell, H. H. Freeze, S. Ostrand-Rosenberg, and G. Srikrishna Proinflammatory S100 Proteins Regulate the Accumulation of Myeloid-Derived Suppressor Cells J. Immunol., October 1, 2008; 181(7): 4666 - 4675. [Abstract] [Full Text] [PDF]

				P. Cheng, C. A. Corzo, N. Luetteke, B. Yu, S. Nagaraj, M. M. Bui, M. Ortiz, W. Nacken, C. Sorg, T. Vogl, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein J. Exp. Med., September 29, 2008; 205(10): 2235 - 2249. [Abstract] [Full Text] [PDF]

				E. Huarte, J. R. Cubillos-Ruiz, Y. C. Nesbeth, U. K. Scarlett, D. G. Martinez, R. J. Buckanovich, F. Benencia, R. V. Stan, T. Keler, P. Sarobe, et al. Depletion of Dendritic Cells Delays Ovarian Cancer Progression by Boosting Antitumor Immunity Cancer Res., September 15, 2008; 68(18): 7684 - 7691. [Abstract] [Full Text] [PDF]

				M. Egeblad, A. J. Ewald, H. A. Askautrud, M. L. Truitt, B. E. Welm, E. Bainbridge, G. Peeters, M. F. Krummel, and Z. Werb Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy Dis. Model. Mech., September 1, 2008; 1(2-3): 155 - 167. [Abstract] [Full Text] [PDF]

				K. Nonaka, M. Saio, T. Suwa, A. B. Frey, N. Umemura, H. Imai, G.-F. Ouyang, S. Osada, M. Balazs, R. Adany, et al. Skewing the Th cell phenotype toward Th1 alters the maturation of tumor-infiltrating mononuclear phagocytes J. Leukoc. Biol., September 1, 2008; 84(3): 679 - 688. [Abstract] [Full Text] [PDF]

				F. Shojaei and N. Ferrara Refractoriness to Antivascular Endothelial Growth Factor Treatment: Role of Myeloid Cells Cancer Res., July 15, 2008; 68(14): 5501 - 5504. [Abstract] [Full Text] [PDF]

				G. Willimsky, M. Czeh, C. Loddenkemper, J. Gellermann, K. Schmidt, P. Wust, H. Stein, and T. Blankenstein Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness J. Exp. Med., July 7, 2008; 205(7): 1687 - 1700. [Abstract] [Full Text] [PDF]

				A.-S. Dugast, T. Haudebourg, F. Coulon, M. Heslan, F. Haspot, N. Poirier, R. Vuillefroy de Silly, C. Usal, H. Smit, B. Martinet, et al. Myeloid-Derived Suppressor Cells Accumulate in Kidney Allograft Tolerance and Specifically Suppress Effector T Cell Expansion J. Immunol., June 15, 2008; 180(12): 7898 - 7906. [Abstract] [Full Text] [PDF]

				N. Umemura, M. Saio, T. Suwa, Y. Kitoh, J. Bai, K. Nonaka, G.-F. Ouyang, M. Okada, M. Balazs, R. Adany, et al. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics J. Leukoc. Biol., May 1, 2008; 83(5): 1136 - 1144. [Abstract] [Full Text] [PDF]

				K. Movahedi, M. Guilliams, J. Van den Bossche, R. Van den Bergh, C. Gysemans, A. Beschin, P. De Baetselier, and J. A. Van Ginderachter Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity Blood, April 15, 2008; 111(8): 4233 - 4244. [Abstract] [Full Text] [PDF]

				C. Melani, S. Sangaletti, F. M. Barazzetta, Z. Werb, and M. P. Colombo Amino-Biphosphonate Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor Stroma Cancer Res., December 1, 2007; 67(23): 11438 - 11446. [Abstract] [Full Text] [PDF]

				Y. Nefedova, M. Fishman, S. Sherman, X. Wang, A. A. Beg, and D. I. Gabrilovich Mechanism of All-Trans Retinoic Acid Effect on Tumor-Associated Myeloid-Derived Suppressor Cells Cancer Res., November 15, 2007; 67(22): 11021 - 11028. [Abstract] [Full Text] [PDF]

				P. C. Kousis, B. W. Henderson, P. G. Maier, and S. O. Gollnick Photodynamic Therapy Enhancement of Antitumor Immunity Is Regulated by Neutrophils Cancer Res., November 1, 2007; 67(21): 10501 - 10510. [Abstract] [Full Text] [PDF]

				R. Marhaba, M. Vitacolonna, D. Hildebrand, M. Baniyash, P. Freyschmidt-Paul, and M. Zoller The Importance of Myeloid-Derived Suppressor Cells in the Regulation of Autoimmune Effector Cells by a Chronic Contact Eczema J. Immunol., October 15, 2007; 179(8): 5071 - 5081. [Abstract] [Full Text] [PDF]

				E. Celis Toll-like Receptor Ligands Energize Peptide Vaccines through Multiple Paths Cancer Res., September 1, 2007; 67(17): 7945 - 7947. [Abstract] [Full Text] [PDF]

				P. Sinha, V. K. Clements, S. K. Bunt, S. M. Albelda, and S. Ostrand-Rosenberg Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response J. Immunol., July 15, 2007; 179(2): 977 - 983. [Abstract] [Full Text] [PDF]

				M. J. Delano, P. O. Scumpia, J. S. Weinstein, D. Coco, S. Nagaraj, K. M. Kelly-Scumpia, K. A. O'Malley, J. L. Wynn, S. Antonenko, S. Z. Al-Quran, et al. MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis J. Exp. Med., June 11, 2007; 204(6): 1463 - 1474. [Abstract] [Full Text] [PDF]

				G. Krystal, L. Sly, F. Antignano, V. Ho, J. Ruschmann, and M. Hamilton Re: The Terminology Issue for Myeloid-Derived Suppressor Cells Cancer Res., April 15, 2007; 67(8): 3986 - 3986. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gabrilovich, D. I. Articles by Schreiber, H. Search for Related Content PubMed PubMed Citation Articles by Gabrilovich, D. I. Articles by Schreiber, H.