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Myeloid suppressor cells regulate the adaptive immune response to cancer
Alan B. Frey
Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
Address correspondence to: Alan B. Frey, Department of Cell Biology, Room MSB 623, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. Phone: (212) 263-8129; Fax: (212) 263-8139; E-mail: freya01@med.nyu.edu.
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Published October 2, 2006 - More info
J Clin Invest. 2006;116(10):2587–2590. https://doi.org/10.1172/JCI29906.
© 2006 The American Society for Clinical Investigation
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Abstract
Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor α+ (CD11b+IL-4Rα+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-γ released from T lymphocytes. CD11b+IL-4Rα+ cells produced IL-13 and IFN-γ and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions.
Authors
Giovanna Gallina, Luigi Dolcetti, Paolo Serafini, Carmela De Santo, Ilaria Marigo, Mario P. Colombo, Giuseppe Basso, Frank Brombacher, Ivan Borrello, Paola Zanovello, Silvio Bicciato, Vincenzo Bronte
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MSCs in cancer
Recent research has focused on deciphering the role played by MSCs in the subversion, inhibition, or downregulation of the immune response to cancer (reviewed in ref. 6). MSCs are uniformly CD11b+TCR– but express surface markers indicative of a mix of partially differentiated monocytes and DCs. The exact differentiation status of MSCs probably reflects the mechanism by which their immunosuppressive function may manifest, as discussed below, and is therefore important to determine. However, this is difficult to establish with precision since the function and phenotype of MSCs may vary in different body compartments. Also, as shown by Kusmartsev and colleagues, MSCs are metabolically plastic, evidenced by their ability to differentiate under the influence of select cytokines and differentiation factors into more mature cell types both in vitro and in vivo (8). Significantly, forced maturation of MSCs in vivo was associated with enhancement of vaccination efficacy, suggesting a potentially novel therapeutic strategy that others may reproduce and even expand upon. In an earlier study, deletion of MSCs in tumor-bearing mice using an antibody to the granulocyte marker Gr-1/Ly6G resulted in enhanced immune responses to tumors (9). That report helped to highlight a role for MSCs in regulation of antitumor immune responses in vivo, but use of Ly6G as a target for MSC depletion may be impossible because this antigen is not necessarily expressed on all functional MSCs. Ly6G is also expressed on neutrophils, which if depleted might confer enhanced susceptibility to microbial infection in patients.
Not only are the differentiation and activation of MSCs incompletely understood, but because MSCs express a veritable cornucopia of pharmacologic agents (including reactive nitrogen and oxygen species, cytokines, proteases, and enzymes important in amino acid metabolism) that can mediate a variety of responses, they have been considered to suppress T cell immune responses via potentially multiple different mechanisms. The study by Gallina and colleagues in this issue of the JCI has significantly clarified several issues in the MSC field and suggests unanticipated strategies for immunotherapy (10). The authors demonstrate that, upon activation by CD8+ T cell–secreted IFN-γ, MSCs produce both IL-13 and IFN-γ, which are utilized in an autocrine manner to enhance the production and activity of 2 enzymes involved in l-arginine (l-Arg) metabolism: iNOS and Arginase I (Figure 1). iNOS produces nitric oxide, which has been shown to interfere with IL-2 receptor signaling such that JAK-1 and -3, STAT-5, and ERK are not activated, leading to cell cycle arrest (11, 12). High arginase I activity depletes l-Arg from the microenvironment and, since activated CD8+ T cells are particularly sensitive to l-Arg levels (13), may result in their functional inactivation. Additionally, it has been shown by the Ochoa lab that CD3ζ is lost in T cells exposed to low l-Arg levels (14), a condition postulated to be extant in the tumor microenvironment, which is typically richly infiltrated with MSCs. However, this mechanism put forth to explain dysfunctional tumor-infiltrating lymphocytes has not been observed by others (5, 15–17), and it remains unclear whether T cell loss of CD3ζ is restricted to particular types of tumors or to particular types of biochemical analysis.
Figure 1Immunosuppressive effects of tumor-induced MSCs on antitumor CD8+ T lymphocytes. Previous work has shown that certain factors that enhance myelopoiesis are produced either by tumors or in response to tumor growth (i). In this issue of the JCI, Gallina et al. (10) demonstrate that release of IFN-γ by CD8+ T lymphocytes (ii) triggers MSCs to release IL-13 and IFN-γ (iii). This results in the production and activation in an autocrine manner of the enzymes iNOS and Arginase I (iv), the downstream effects of which can inhibit CD8+ T cell proliferation and activation or trigger T cell apoptosis (v). Therapeutic approaches to lifting this MSC-induced immunosuppression during cancer might include targeted deletion of IL-4Rα+ cells (MSCs), blockade of IL-4Rα, inhibition of STAT-3–dependent pre-MSC maturation into active MSCs, and Arginase I or iNOS inhibition. Figure modified from Gallina et al. (10).
Another major finding of the current study (10) is that MSCs express IL-4 receptor α (IL-4Rα), an observation that may be useful for the targeted deletion or inactivation of MSCs in vivo. It may also provide an explanation for the observation by Terabe and colleagues that, in murine models, NKT cells producing IL-13 (which shares usage of the IL-4Rα with IL-4) caused secretion of TGF-β from MSCs and inhibition of antitumor CTLs (18). In their tumor recurrence model, Terabe et al. showed that MSCs produced 2-fold higher TGF-β levels in vitro than did nonlymphoid splenocytes isolated from control (non–tumor bearing) mice (18). Administration of neutralizing anti–TGF-β protected mice from tumor recurrence, implying a role for TGF-β in suppression of antitumor immune responses; the kinetics of the effect suggested a role for TGF-β in inhibition of antitumor CTLs. Although they conclude the use of a different biochemical mediator of T cell suppression than Terabe et al., Gallina et al. did not address a role for TGF-β in their study, so it is a reasonable possibility that MSCs can utilize multiple biochemical mediators of suppression.
Through the use of strains of mice wherein expression of select cytokines, cytokine receptors, or CD1 was abrogated by gene inactivation, Gallina et al. (10) show that neither NK nor NKT cells are required to elicit or activate MSCs. Although the phenotype of CD1d-restricted NKT cells can vary in strains of distinct genetic backgrounds, favoring Th2 polarization in BALB/c and Th1 in C57BL/6 mice (19), the disparate results of Gallina et al. and Terabe et al. (18) cannot be explained by strain differences since both studies used BALB/c mice. Thus, the basis for this essential difference remains unclear and may reflect a differential requirement for NKT cells due to different levels of systemic GM-CSF in the 2 models; inherent differences in the nature of the host immune response to the different tumors used; the kinetics of host response such that NKT cells participate in immune suppression at early times of tumor growth but not in later stages; or the fact that Terabe and colleagues strongly stimulated T cells before measurement of cytokine production (20), whereas Gallina et al. assayed IL-13 and IFN-γ production from unstimulated MSCs.
Because expression of Arginase I and iNOS is reciprocally influenced by Th1 and Th2 cytokines, it has been suggested that activation of each is restricted to separate subsets of myeloid-derived cells, termed alternative activation (21–23). Clearly though, both enzymes are produced in CD11b+IL-4Rα+ MSCs, and MSCs produce both Th1-type and Th2-type cytokines (IL-13 and IFN-γ). Therefore, the designation “alternatively activated” may not be applicable or relevant in the characterization of MSCs. More important than the semantic concerns is derivation of the mechanism that MSCs utilize to inactivate T cell functions. The determination that MSCs produce both Arginase I and iNOS provides insights that can be potentially translated to the clinic. Under conditions of low l-Arg together with activation of iNOS, superoxide is produced (24), which can react with nitric oxide and produce highly reactive peroxynitrites, which can in turn nitrosylate susceptible amino acid side chains, especially tyrosine (25). If proteins important in T cell signaling are inactivated by nitrosylation, both effector phase functions and differentiation will be abrogated. The demonstration that MSCs exert this complex biochemical scenario, together with the observation that inhibition of Arginase I and iNOS restores T cell function (5), strongly supports the mechanism of MSC function postulated in the current study by Gallina et al. (10). Proof positive will be the identification of T cell signaling proteins in tumor-infiltrating lymphocytes that are specifically nitrosylated.
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