Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity
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Myeloid-derived suppressor cells (MDSC) accumulate in most cancer patients and experimental animals with cancer. They accumulate in response to pro-inflammatory mediators and they use a variety of mechanisms to block both innate and adaptive antitumor immunity. Because of their critical role in obstructing immune responses, MDSC are a strategic obstacle to immunotherapies that require activation of the host’s cell-mediated and innate immune responses. Following a brief description of the factors that induce MDSC accumulation, this article reviews two newly discovered mechanisms that MDSC use to suppress the activation of CD4+ and CD8+ T cells. The first mechanism is MDSC sequestration of cysteine, an amino acid that T cells are unable to synthesize de novo and that they require for activation. The second mechanism is MDSC-mediated down-regulation of l-selectin. T cells must have an l-selectinhigh phenotype to home to lymph nodes and inflammatory sites where they encounter antigen and are activated. By down-regulating l-selectin on T cells, MDSC perturb T cell trafficking patterns and thereby inhibit T cell activation. Given the complexity of conditions that regulate MDSC accumulation and the variety of suppressive mechanisms used by MDSC, it is essential to understand which conditions and mechanisms are dominant so MDSC accumulation and/or activity can be targeted in individual patients to minimize MDSC-induced immune suppression.
KeywordsTumor-induced immune suppression Amino acid metabolism T cell trafficking Suppressive myeloid cells
These studies were supported by National Institutes of Health Grants RO1CA115880 and RO1CA84232. Animal studies described herein were approved by the UMBC Institutional Animal Care and Use Committee.
Conflict of interest statement
The author has no conflict of interest with the organization sponsoring this research.
- 6.Pak AS, Wright MA, Matthews JP, Collins SL, Petruzzelli GJ, Young MR (1995) Mechanisms of immune suppression in patients with head and neck cancer: presence of CD34(+) cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res 1:95–103PubMedGoogle Scholar
- 7.Young MR, Wright MA (1992) Myelopoiesis-associated immune suppressor cells in mice bearing metastatic Lewis lung carcinoma tumors: gamma interferon plus tumor necrosis factor alpha synergistically reduces immune suppressor and tumor growth-promoting activities of bone marrow cells and diminishes tumor recurrence and metastasis. Cancer Res 52:6335–6340PubMedGoogle Scholar
- 14.Terabe M, Matsui S, Park JM, Mamura M, Noben-Trauth N, Donaldson DD, Chen W, Wahl SM, Ledbetter S, Pratt B, Letterio JJ, Paul WE, Berzofsky JA (2003) Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 198:1741–1752CrossRefPubMedGoogle Scholar
- 19.Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI (2008) Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205:2235–2249CrossRefPubMedGoogle Scholar
- 22.Terabe M, Swann J, Ambrosino E, Sinha P, Takaku S, Hayakawa Y, Godfrey DI, Ostrand-Rosenberg S, Smyth MJ, Berzofsky JA (2005) A nonclassical non-Valpha14Jalpha18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. J Exp Med 202:1627–1633CrossRefPubMedGoogle Scholar
- 23.De Santo C, Salio M, Masri SH, Lee LY, Dong T, Speak AO, Porubsky S, Booth S, Veerapen N, Besra GS, Grone HJ, Platt FM, Zambon M, Cerundolo V (2008) Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest 118:4036–4048CrossRefPubMedGoogle Scholar
- 24.Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O’Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL (2007) MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med 204:1463–1474CrossRefPubMedGoogle Scholar
- 25.Haile LA, von Wasielewski R, Gamrekelashvili J, Kruger C, Bachmann O, Westendorf AM, Buer J, Liblau R, Manns MP, Korangy F, Greten TF (2008) Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. Gastroenterology 135:871–881 (881 e1−5)CrossRefPubMedGoogle Scholar
- 26.Brys L, Beschin A, Raes G, Ghassabeh GH, Noel W, Brandt J, Brombacher F, De Baetselier P (2005) Reactive oxygen species and 12/15-lipoxygenase contribute to the antiproliferative capacity of alternatively activated myeloid cells elicited during helminth infection. J Immunol 174:6095–6104PubMedGoogle Scholar
- 27.Angulo I, de las Heras FG, Garcia-Bustos JF, Gargallo D, Munoz-Fernandez MA, Fresno M (2000) Nitric oxide-producing CD11b(+)Ly-6G(Gr-1)(+)CD31(ER-MP12)(+) cells in the spleen of cyclophosphamide-treated mice: implications for T-cell responses in immunosuppressed mice. Blood 95:212–220PubMedGoogle Scholar
- 31.Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, De Baetselier P, Van Ginderachter JA (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111:4233–4244CrossRefPubMedGoogle Scholar
- 33.Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev ImmunolGoogle Scholar
- 47.Ezernitchi AV, Vaknin I, Cohen-Daniel L, Levy O, Manaster E, Halabi A, Pikarsky E, Shapira L, Baniyash M (2006) TCR zeta down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J Immunol 177:4763–4772PubMedGoogle Scholar