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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4696-4697 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.3116
In ReplyUnit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
Unit of Immunobiotherapy of Solid Tumors S. Raffaele Scientific Institute, Milan, Italy A growing body of evidence currently supports the role of myeloid suppressor cells (MSC) as key mediators of immunosuppression in tumor-bearing animals.1 Nevertheless, the analysis of the actual relevance of this mechanism in cancer patients has so far been penalized by the variability of phenotypic and functional hallmarks that these cells appear to display in a human setting. In our study, we identify a monocyte subset (CD14+ human leukocyte antigen-DR [HLA-DR]–/lo transforming growth factor-β [TGF-β]–secreting cells) that may indeed represent an MSC population in patients with advanced melanoma. The finding acquires more relevance considering that melanoma is one of the human tumor histotypes mostly involved in immunotherapy studies because of its unique immunogenic properties.2 Having defined features for the identification of MSC in patients with melanoma should allow us in the near future to understand the relevance that this cell subset plays in restraining antitumor immune responses. Indeed, the increased number of CD14+HLA-DR–/lo MSC in melanoma patients receiving low-dose granulocyte-macrophage colony-stimulating factor, a growth factor known to cause MSC recruitment and mobilization,1 was associated with poor immunological responses to an antimelanoma vaccine given concomitantly, proving the detrimental effect of MSC on T-cell reactivity.
According to our data, the mechanism by which CD14+HLA-DR–/lo MSC exert their suppressive effect on lymphocyte proliferation and effector function (ie, expression of perforin and interferon gamma [IFN
As correctly pointed out by Ferretti, TGF-β is a pathway shared by different regulatory immune mechanisms. Indeed, regulatory T cells (Treg) exert their immunosuppressive activity through mechanisms including cell-cell contact and/or the production of soluble factors such as interleukin-10 or TGF-β,3 as we are presently observing in advanced melanoma patients (Castelli et al, unpublished observation, 2007). Recent studies in experimental models have linked MSC to Treg, showing that the conversion by tumor cells of dendritic cells into MSC induces bioactive TGF-β secretion, which in turn stimulates Treg expansion and subsequent suppression of T cell–mediated immune responses.4 This pathway depends on the presence of IFN Although fascinating, the occurrence of an MSC/Treg cross-activation comparable to that described in murine models4,5 has not been reported in cancer patients thus far. Nevertheless, we looked for signs of this pathway and found that the increase of MSC frequency and immunosuppressive activity observed in peripheral blood of advanced melanoma patients treated with the granulocyte-macrophage colony-stimulating factor–based vaccine was not associated with any expansion of CD4+CD25+Foxp3+ Treg cells (P. Filipazzi, unpublished observation, 2006). Similarly, in our in vitro model of MSC generation, consisting of the generation of CD14+HLA-DR–/lo TGF-β–producing cells on incubation of CD14+ monocytes with melanoma-derived exosomes,6 we found that suppression of lymphocyte proliferation was not associated with any significant boost of Treg frequency (R. Valenti, unpublished data, 2006). Although the absence of quantitative changes does not exclude the occurrence of qualitative modifications in the activation state of these cells, our data do not support a direct connection between MSC expansion and Treg activation. Nevertheless, from our study as well as from several other works,7,8 TGF-β is emerging as a cytokine playing a pivotal role in immunosuppression of cancer patients. Indeed, both MSC and Treg seem to use this pathway to shut down antitumor T cell responses; therefore, interfering with the activity of this cytokine could represent a key strategy to cancer therapy. New molecules such as antisense oligonucleotides for TGF-β, small drug-molecules that inhibit TGF-β receptor I kinase, and anti–TGF-β antibodies have shown promising results in preclinical studies and are presently entering the clinical phase of evaluation.9 However, having TGF-β—a known double-edged function in cancer10,11—acting as tumor promoter and tumor suppressor as well, therapeutic approaches should aim exclusively to inhibit its function in tumor progression, while retaining the growth-inhibitory and apoptosis-inducing properties. Alternatively, the interference with immunosuppressive mechanisms could be attempted upstream, interfering with the pathway utilized by tumor cells to promote MSC in vivo generation. As we reported that exosomes released by melanoma cells are likely responsible for the induction of CD14+HLA-DR–/lo cells secreting TGF-β,6 thwarting the process of exosome production could represent a tool for interrupting the immunosuppressive circuits established by tumor cells and for retrieval of cancer immunity.12 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Serafini P, Borrello I, Bronte V: Myeloid suppressor cells in cancer: Recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16:53-65, 2006[CrossRef][Medline] 2. Parmiani G, Castelli C, Santinami M, et al: Melanoma immunology: Past, present and future. Curr Opin Oncol 19:121-127, 2007[Medline] 3. Curiel TJ: Tregs and rethinking cancer immunotherapy. J Clin Invest 117:1167-1174, 2007[CrossRef][Medline] 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. 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 66:1123-1131, 2006 6. Valenti R, Huber V, Filipazzi P, et al: Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 66:9290-9298, 2006 7. Wahl SM, Wen J, Moutsopoulos N: TGF-beta: A mobile purveyor of immune privilege. Immunol Rev 213:213-227, 2006[CrossRef][Medline] 8. Elliott RL, Blobe GC: Role of transforming growth factor Beta in human cancer. J Clin Oncol 23:2078-2093, 2005 9. Kirkbride KC, Blobe GC: Inhibiting the TGF-beta signalling pathway as a means of cancer immunotherapy. Expert Opin Biol Ther 3:251-261, 2003[Medline] 10. Akhurst RJ, Derynck R: TGF-beta signaling in cancer–a double-edged sword. Trends Cell Biol 11(11):S44-51, 2001 11. Siegel PM, Massague J: Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3:807-821, 2003[CrossRef][Medline] 12. Valenti R, Huber V, Iero M, et al: Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 67:2912-2915, 2007
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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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] production) is unequivocally linked to the release of TFG-β, without any detectable involvement of the alternative suppressive pathways described instead for murine MSC (ie, those mediated by arginase or inducible nitric oxide synthase metabolism products). 
