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Cutting Edge: Th17 and Regulatory T Cell Dynamics and the Regulation by IL-2 in the Tumor Microenvironment¹

Ilona Kryczek^*, Shuang Wei^*, Linhua Zou^*, Saleh Altuwaijri^*, Wojciech Szeliga^*, Jay Kolls, Alfred Chang^* and Weiping Zou^2,*

^* Department of Surgery, University of Michigan, Ann Arbor, MI 48109; and Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213

	Abstract

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Th17 cells play an active role in inflammation and autoimmune diseases. However, the nature and regulation of Th17 in the context of tumor immunity remain unknown. In this study, we show that parallel to regulatory T (Treg) cells, IL-17⁺ CD4⁺ and CD8⁺ T cells are kinetically induced in multiple tumor microenvironments in mice and humans. Treg cells play a crucial role in tumor immune pathogenesis and temper immune therapeutic efficacy. IL-2 is crucial for the production and function of Treg cells. We now show that IL-2 reduces IL-17⁺ T cell differentiation in the tumor microenvironment accompanied with an enhanced Treg cell compartment in vitro and in vivo. Altogether, our work demonstrates a dynamic differentiation of IL-17⁺ T cells in the tumor microenvironment, reveals a novel role for IL-2 in controlling the balance between IL-17⁺ and Treg cells, and provides new insight of IL-17⁺ T cells in tumor immune pathology and therapy.

	Introduction

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The range of effector CD4⁺ T cell lineages has been expanded with a description of an IL-17-producing subpopulation called Th17. Th17 cells and IL-17 play an active role in the inflammation and autoimmune diseases in murine systems (1, 2, 3, 4, 5, 6, 7, 8). IL-23 and IL-1 may be important for amplifying and stabilizing the Th17 phenotype in chronic inflammation (2, 4, 5, 6, 9, 10, 11, 12). Dendritic cells transduced with IL-23 promote antitumor immunity (13). Strikingly, it was also reported that IL-23 may promote tumor incidence and growth (14). Although these data may suggest a potential impact of Th17 cells on tumor, the nature, regulation, and role of Th17 in the context of tumor immunity remain unknown both in mice and humans.

	Materials and Methods

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Mice and tumors

All mouse procedures were performed in accordance with institutional protocol guidelines at the University of Michigan under an approved protocol. TRAMP C57BL/6 mice (8- to 10-wk-old males) and wild-type C57BL/6 mice (4- to 8-wk-old females) were obtained from The Jackson Laboratory. Prostate tumor developed in TRAMP C57BL/6 mice was used for T cell phenotyping. The B16 mouse melanoma (B16), and the head and neck squamous cell carcinoma (SCC7) cell lines were obtained from American Type Culture Collection. Mouse 3-methylcholanthrene-induced fibrosarcomas (MCA207) were maintained in vivo by serial subcutaneously transplantation in C57BL/6 mice and were used within the eighth transplantation generation. B16, HN, and MCA tumors were established in C57BL/6 mice by intradermal inoculation of 1.5 x 10⁶ tumor cells. For experiments requiring two tumors on the same mouse, tumors were given on the left and right flank. In some cases, C57BL/6 mice bearing B16 were received by i.p. injection of IL-2 every 3 days (5 µg/animal). Tumor, blood, lymph nodes, and spleen were collected for analyzing T cell phenotype and cytokine profile as we described (15, 16).

Human tumors

Fresh human tumor tissues were obtained from previously untreated patients with epithelial ovarian carcinomas, renal cell carcinoma, and pancreatic carcinoma in stage III or IV. Patients gave written, informed consent. The study was approved by local Institutional Review Boards.

In vitro culture system

T cells were isolated from the spleen of C57BL/6 mice with a commercial kit (Stem Cell Technology) and stimulated with 2.5 µg/ml anti-CD3 and 1.2 µg/ml anti-CD28 (BD Biosciences) for 3 days in the presence of cytokines TGF-1 (10 ng/ml), IL-6 (10 ng/ml), IL-2 (50 ng/ml) (all obtained from R&D Systems), or neutralizing anti-IL-2 mAb (3 µg/ml, S4B6; BD Biosciences). Cells were subjected to T cell phenotyping.

T cell phenotype and cytokine profile

T cells were collected from tumor tissues and multiple organs were stimulated for 4 h with leukocyte activation cocktail (BD Biosciences) in the presence of either GolgiStop (BD Biosciences). Cells were first stained extracellularly with anti-CD4, anti-CD8, and anti-CD90 for mouse or anti-CD3 for humans (BD Biosciences), then were fixed and permeabilized with Perm/Fix solution (eBiosciences), and finally were stained intracellularly with anti-IFN- (BD Bioscience), anti-IL-17 (BD Biosciences and eBioscience), and anti-FOXP3 (eBioscience). Samples were acquired on a LSR II (BD Biosciences), and data were analyzed with DIVA software (BD Biosciences).

Statistical calculations

Differences in cell surface and intracellular molecule expression were determined by an ² test, with p < 0.05 considered significant.

	Results and Discussion

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In the first experimental setting, we studied IL-17⁺ T cells in multiple mouse and human tumors. We initially evaluated the potential existence and organ distribution of IL-17⁺ T cells in normal vs mice bearing advanced B16 melanoma. We found that the levels of IL-17⁺ T cells were limited (<1.5%) in different compartments in normal mice. Interestingly, the levels of IL-17⁺ T cells (3–8%) were significantly increased in blood, bone marrow, and spleen in mice bearing advanced B16 melanoma, but not in the tumor draining lymph nodes (Fig. 1a). More strikingly, the highest levels of IL-17⁺ T cells (average: 12%, range: 2–45%) were found in the tumor tissues (Fig. 1a).

View larger version (44K): [in this window] [in a new window]   FIGURE 1. IL-17+ T cells in multiple mouse and human tumors. a, gIL-17+ T cells in normal vs tumor bearing mice. Single cell suspension was obtained from tumor tissues and multiple organs in mice bearing day 19 mouse B16 melanoma. Age-matched normal mice served as controls. The single cells were subjected to staining with the indicated Abs and analyzed with LSR II. Results were shown as the percentage of IL-17+IFN-– cells in T cells. One of 8 to 12 organs or tumors per group is shown. b, IL-17+ T cells in multiple mouse tumors. Single cell suspension was obtained from tumor tissues in mice bearing advanced head and neck tumor, melanoma, prostate cancer, and MCA. The single cells were subjected to staining with the indicated Abs and analyzed with LSR II. Results were expressed as the percentage of IL-17+ cells in CD4+ or CD8+ T cells. One of 4 to 6 tumors per group is shown. c, IL-17+ T cells in multiple human tumors. Single cell suspension was obtained from human peripheral blood (PBMC), tumor tissues, and ovarian cancer ascites. The single cells were subjected to staining with the indicated Abs and analyzed with LSR II. Results were expressed as the percentage of IL-17+ cells in T cells. One of 2 to 5 tumors per group is shown.

Th17 cells have not been studied in human subjects with cancer. We next examined the potential existence and distribution of IL-17⁺ T cells in normal healthy donors vs multiple cancer patients. Consistent with our observations in mice (Fig. 1, a and b), we showed that there were limited IL-17⁺ T cells (<1.2%) in peripheral blood in normal donors. However, the levels of IL-17⁺ T cells were significantly increased in peripheral blood in patients with advanced ovarian carcinoma. Whereas the highest levels of IL-17⁺ T cells were detected in the tumor tissues in patients with advanced ovarian (including tumor tissue and malignant ascites fluid), pancreatic, and renal cell carcinoma (Fig. 1c).

High levels of regulatory T (Treg)³ cells are found in the tumor microenvironment and Treg cells play a crucial role in tumor immunity (16, 17, 18, 19, 20). We further studied the kinetic distribution of IL-17⁺ T cells and the relationship with CD4⁺FOXP3⁺ Treg cells in tumor and multiple organs in mice bearing B16 melanoma. We observed that the number of CD4⁺IL-17⁺ T cells and CD4⁺FOXP3⁺ Treg cells (Fig. 2, a and b) was gradually and synchronically increased in the tumor microenvironment during tumor development. However, there were limited IL-17⁺CD8⁺ T cells in the early stages of tumor growth with greater numbers of IL-17⁺CD8⁺ T cells appearing in later stages of tumor development (Fig. 2a). Although the trend of increase was similar between Treg cells and IL-17⁺CD4⁺ T cells in the tumor, the prevalence of Treg cells was significantly and constantly higher than that of IL-17⁺ T cells in the tumor (Fig. 2, a and b).

View larger version (35K): [in this window] [in a new window]   FIGURE 2. Kinetic distribution of IL-17+ T cells and Treg cells in the tumor microenvironment. Kinetic distribution of Th17 and Treg cells in tumors (a and b) or tumor draining lymph nodes (c and d). Single cell suspension was obtained from tumor or tumor draining lymph node tissue in mice bearing B16 melanoma at different time points. The cells were stained with different Abs and analyzed with LSR II. a and c, The results were expressed as the mean percentage ± SEM of FOXP3+ and IL-17+IFN-– cells in CD4+ or CD8+ T cells. Four to 6 mice per time point.

The first part of our findings has demonstrated for the first time several features of these tumor-associated IL-17 expressing T cells. 1) Th17 and Treg cells are synchronically increased following tumor development. Both populations reach the maximal levels in advanced tumors. The kinetic distribution of Treg cells and IL-17⁺ T cells suggests their close relationship in the tumor. The cytokine cocktail of TGF and IL-6 promotes Th17 differentiation (21, 22, 23). In the murine autoimmune system Treg cell-derived TGF supports Th17 cell differentiation (21, 22, 23). High levels of TGF and IL-6 are often found in advanced tumors (19). Cytokines in the tumor microenvironment should support Th17 differentiation within the tumor. However, the levels of Treg cells are significantly and constantly higher than IL-17⁺ T cells in the tumor environment. It suggests that IL-17⁺ T cell differentiation may be inhibited by unknown factor(s) in the tumor microenvironment. 2) In advanced tumors there are IL-17⁺CD4⁺ T cells (Th17 cells) as well as substantial amounts of IL-17⁺CD8⁺ T cells. The data suggest the potential role of a previously unappreciated IL-17 expressing T cell population, IL-17⁺CD8⁺ T cells in tumor immunopathogenesis. It remains to be defined whether IL-17⁺CD8⁺ T cells are a unique feature in tumors. 3) IL-17 expressing T cells are largely found in the tumor, particularly in advanced tumors, not in the tumor draining lymph nodes. It suggests that IL-17⁺ T cells may be predominantly differentiated in the tumor microenvironment, rather than in the draining lymph nodes. 4) Similar dynamic distribution and compartmentalization of IL-17⁺ T cells are observed in multiple mouse and human tumor models. It suggests a potential broad involvement of IL-17⁺ T cells in tumor pathogenesis. Thus, our data provide the first evidence of the existence of the IL-17 expressing T cells in mouse and human tumors including both CD4⁺ and CD8⁺ T cells, and demonstrate the kinetic distribution and relationship between Treg cells and IL-17⁺ T cells.

IL-2 is crucial for the production and function of Treg cells in mice (24, 25, 26) and cancer patients (27, 28). IL-2 is used to boost immunity in patients with cancer (29, 30). We investigated the potential effects of IL-2 on IL-17⁺ T cell differentiation. It was reported in mouse models that TGF promotes Treg cell differentiation whereas TGF plus IL-6 stimulates Th17 cell differentiation. To generate Th17 cells, we cultured mouse spleen T cells with TGF and IL-6. Consistent with previous reports (21, 22, 23), TGF and IL-6 stimulated IL-17⁺CD4⁺ cell differentiation (Fig. 3, a and b). TGF and IL-6 also strongly stimulated IL-17⁺CD8⁺ cell differentiation (Fig. 3c). Exogenous IL-2 profoundly reduced the percentage of IL-17⁺CD4⁺ cells in CD4⁺ cells and of IL-17⁺CD8⁺ cells in CD8⁺ cells in the culture (Fig. 3, a–c). The absolute numbers of IL-17⁺CD4⁺ cells (27 ± 19%, compared with control) and IL-17⁺CD8⁺ cells (23 ± 17%, compared with control) were reduced nearly 4-fold by IL-2 treatment. Blockade of IL-2 with neutralizing anti-IL-2 mAb dramatically increased Th17 and IL-17⁺CD8⁺ cell differentiation (Fig. 3, a–c).

View larger version (37K): [in this window] [in a new window]   FIGURE 3. Opposite effects of IL-2 on IL-17+ T cell and Treg cell differentiation. a–c, Effects of IL-2 on IL-17+IFN-– T cell differentiation in vitro. Spleen T cells were cultured for 3 days with TGF and IL-6 in the presence of IL-2 or neutralizing anti-IL-2 mAb. The resulting T cells were analyzed with LSR II for the expression of IL-17 and IFN-. a, Results were expressed as the mean ± SEM of IL-17+IFN-– cells in T cells (n = 6, *, p < 0.01). b and c, IL-17 and IFN- expression were further analyzed in CD8+ and CD4+ T cells subpopulation. One representative of 6 experiments is shown. d, Effects of IL-2 on FOXP3+CD4+ T cell differentiation in vitro. Spleen T cells were cultured 3 days with TGF- in the presence of IL-2 or neutralizing anti-IL-2 mAb. The resulting T cells were analyzed with LSR II for the expression of FOXP3. Results were expressed as the percentage of FOXP3+ cells in CD4+ T cells. (n = 6, *, p < 0.01). e and f, Effects of IL-2 on IL-17+IFN-– and FOXP3+CD4+ T cell differentiation in vivo. B16 melanoma bearing mice were treated with IL-2 as described in Materials and Method. T cells were obtained from day 8 tumor tissues and tumor draining lymph nodes, and analyzed with LSR II for the expression of IL-17, IFN-, and FOXP3. Results were expressed as the mean percentage of IL-17+IFN-– (e) or CD4+FOXP3+ cells ± SEM in CD4+ T cells (f) (n = 5–8 per group, *, p < 0.05). LNs, lymph nodes.

We next examined the in vivo effects of IL-2 on IL-17⁺ T cell and Treg cell differentiation in vivo in mice bearing B16 tumor. Tumor bearing mice were treated with IL-2. We observed that IL-2 significantly reduced IL-17⁺ T cells in the tumor, but not in the draining lymph nodes, whereas FOXP3⁺ T cells were significantly enhanced in tumor and tumor draining lymph nodes (Fig. 3, e and f). The dose of IL-2 used in this experiment had no significant effects on B16 melanoma growth (data not shown). The data demonstrate the opposite effects of IL-2 on IL-17⁺ T cell and Treg cell differentiation in vivo in tumor bearing host. TGF has been proposed to be the link between Th17 and Treg cells in mouse autoimmune diseases (21, 22, 23). We now propose that IL-2 is a new link between these two T cell types. Treg and Th17 cells play active roles in autoimmune diseases, allergy, organ transplantation, and tumor. Therefore, our data reveal a novel regulatory mechanism for IL-2: IL-2 may play a central role in balancing Treg cells and IL-17⁺ T cells in multiple diseases.

Altogether, our work has demonstrated a dynamic differentiation of IL-17⁺ T cells including CD4⁺ T cells and CD8⁺ T cells in the tumor microenvironment in multiple mouse and human tumors. We have further identified a novel role for IL-2 in regulating the IL-17⁺ T cell pool. It has been reported that IL-23 promotes tumor incidence and tumor growth (14). However, dendritic cells transduced with IL-23 elicit potent tumor immunity (13). IL-23 is associated with the development of Th17 cells in autoimmune disease models (9, 10, 11, 12). It is predicted that IL-17⁺ T cells in the tumor microenvironment may contribute to tumor pathogenesis.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Cancer Institute (W.Z.).

² Address correspondence and reprint requests to Dr. Weiping Zou, University of Michigan School of Medicine, C560B MSRB II, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0669. E-mail: wzou{at}umich.edu

³ Abbreviations used in this paper: Treg, regulatory T; MCA, 3-methylcholanthrene.

Received for publication February 15, 2007. Accepted for publication April 4, 2007.

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Top Abstract Introduction Materials and Methods Results and Discussion Disclosures References

 

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