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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4695-4696 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.2894
Transforming Growth Factor-β Signaling and Regulatory T CellsDivision of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy
Unit of Medical Oncology, Ospedali Riuniti, Bergamo, Italy To the Editor: In their study, Filipazzi et al1 show that CD14+ human leukocyte antigen-DR (HLA-DR)–/lo transforming growth factor-β (TGF-β)–producing cells are increased in melanoma patients compared with healthy donors. Melanoma cells can directly induce the in vitro generation of CD14+HLA-DR–/lo cells with TGF-β–mediated suppressive activity through the release of vesicular organelles.2 CD14+HLA-DR–/lo suppressive activity was mediated by TGF-β, because it could be completely abolished by the addition of a specific neutralizing monoclonal antibody. Conversely, the depletion of CD14+HLA-DR–/lo monocyte subset resulted in enhanced proliferation and improved effector functions in activated T lymphocytes.1 The lack of HLA-DR expression in myeloid cells may identify an immunosuppressive cell subset. Almand et al.3 described murine myeloid suppressor cells as immature myeloid cells expressing low or undetectable levels of major histocompatibility complex (MHC) class II antigens (HLA-DR). The population of immature cells that is increased in the blood of patients with cancer consists of early stage myeloid cells, immature monocytes and dendritic cells (DCs). The expression of costimulatory molecules in tumor-associated DCs consistent with the phenotype of immature DCs is lacking. These cells have a substantially lower level of expression of MHC class II and costimulatory molecules than DCs isolated from control donors. DCs isolated from tumor-bearing mice also had a decreased expression of B7-2 and MHC class II, as well as some adhesion molecules. In contrast, other authors suggest that immature DC-mediated regulatory T (Treg) cell expansion occurring in tumor-bearing hosts is MHC class II–restricted because Treg cell proliferation induced by immature DCs from tumor-bearing rats was abolished by the depletion of MHC class II–expressing cells.4 There is a linear pathway that links tumor progression to immune suppression. Tumor cells license DCs to promote Treg cell proliferation via TGF-β4; tumor cells produce factors that stimulate local immature myeloid DCs to produce TGF-β; TGF-β then acts as a costimulator to drive the proliferation of FOXP3+CD4+CD25+ Treg cells in a TGF-β receptor II–dependent fashion; Treg cells in turn mediate immunosuppression. The data presented by Filipazzi et al1 show that CD14+HLA-DR–/lo TGF-β–producing cells may represent a new component of the murine myeloid suppressor cells population in melanoma patients. The CD14+HLA-DR–/lo monocyte subset exerts its suppressive activity by release of TGF-β. In addition, the presence of suppressive monocytes, a high percentage of CD14+HLA-DR–/lo cells, and a significant increase in TGF-β sera levels were associated with a poor immunologic response to the shock protein peptide complex gp96 (HSPPC-96)/granulocyte-macrophage colony-stimulating factor vaccination. The essential role for TGF-β receptor signaling, either in the maintenance of the peripheral Treg-cell subset or in limiting TH1- and/or TH2-cell and cytolytic T-cell differentiation, or both, could be a reason for the fatal autoimmune lesions observed in Tgfbr2 conditional knockout and Tgfb1–/– mice. In TGF-β receptor II-dominant-negative mice, TGF-β receptor–signaling-deficient T cells are insensitive to Treg-cell–mediated suppression.5,6 In addition, it has been reported that tumor cells directly convert CD4CD25+ T cells to Treg cells through production of high levels of TGF-β, suggesting a possible mechanism through which tumor cells evade the immune system.7 DCs can induce antigen-specific CD4+CD25+Foxp3+ T cells that can inhibit fully developed autoimmunity in a nonlymphopenic host.8 However, regarding the hypothetical mechanisms of TGF-β1–mediated control of effector T cells, several crucial issues remain still open. Whether Treg-cell–mediated suppression and TGF-β receptor–dependent signaling are part of the same mechanism, or whether they are parallel pathways, with TGF-β receptor signaling being separate from, but not the prerequisite for, regulatory T-cell–dependent suppression, is still an issue of debate.9 Another possibility is that different aspects of T-cell activation or even different types of T-cells are controlled independently by these two mechanisms. Future studies are needed to elucidate the relationship between cytokine- and cell-mediated mechanisms of tumor cell escape from the immune system or of protection against T-cell–mediated autoimmunity. Current strategies directed toward selective depletion or inhibition of Treg cells include targeting local tumor and peripheral blood. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Filipazzi P, Valenti R, Huber V, et al: Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25:2546-2553, 2007 2. Valenti R, Huber V, Filipazzi P, et al: Human tumor-released microvesicles promote the differentiation of myeloid cells with TGF-beta-mediated suppressive activity on T lymphocytes. Cancer Res 66:9290-9298, 2006 3. Almand B, Clark JI, Nikitina E, et al: Increased production of immature myeloid cells in cancer patients: A mechanism of immunosuppression in cancer. J Immunol 166:678-689, 2001 4. Ghiringhelli F, Puig PE, Roux S, et al: Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202:919-929, 2005 5. Gorelik L, Flavell RA: Abrogation of TGF signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12:171-181, 2000[CrossRef][Medline] 6. Lucas PJ, Kim SJ, Melby SJ, et al: Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor II receptor. J Exp Med 191:1187-1196, 2000 7. Liu VC, Wong LY, Jang T, et al: Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: Role of tumor-derived TGF-beta. J Immunol 178:2883-2892, 2007 8. Luo X, Tarbell KV, Yang H, et al: Dendritic cells with TGF-beta1 differentiate naive CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 104:2821-2826, 2007 9. Rubtsov YP, Rudensky AY: TGF beta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol 7:443-453, 2007[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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