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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Immunol. Author manuscript; available in PMC Jul 21, 2012.
Published in final edited form as:
PMCID: PMC3401482
Thymic stromal lymphopoietin is a key mediator of breast cancer progression
Purevdorj B. Olkhanud,$ Yrina Rochman,*$ Monica Bodogai,$ Enkhzol Malchinkhuu, Katarzyna Wejksza, Mai Xu, Ronald E. Gress,** Charles Hesdorffer, Warren J. Leonard,*1 and Arya Biragyn1
Immunotherapeutics Unit, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD
*Laboratory of Molecular Immunology, Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
**Experimental Transplantation and Immunology Branch, National Institutes of Health, Bethesda, MD
1Please address correspondence to: Arya Biragyn, Ph.D. National Institute on Aging, 251 Bayview Blvd, Suite 100, Baltimore, Maryland 21224. Ph. (410) 558-8680; Fax: (410) 558-8284: biragyna/at/ or Warren J. Leonard, M.D., National Heart, Lung, and Blood Institute, NIH, Bldg. 10, Rm. 7B05, Bethesda, MD 20892-1674 Ph. (301) 496-0098; Fax: (301) 402-0971: wjl/at/
$P.B.O., Y.R., & M.B. are equal contributors
Inflammation is a double-edged sword that can promote or suppress cancer progression. Here we report that thymic stromal lymphopoietin (TSLP), an IL-7-like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs, is also expressed in human and murine cancers. Our studies with murine cancer cells indicate that TSLP plays an essential role in cancer escape, as its inactivation in cancer cells alone was sufficient to almost completely abrogate cancer progression and lung metastasis. The cancer-promoting activity of TSLP primarily required signaling through the TSLP receptor on CD4+ T cells, promoting Th2-skewed immune responses and production of immunosuppressive factors such as IL-10 and IL-13. Expression of TSLP therefore may be a useful prognostic marker and its targeting could have therapeutic potential.
Keywords: TSLP, breast cancer metastasis, Th2-type responses
Cancer progression and metastasis is a multifaceted process that involves inflammation and the active participation of immune cells, such as myeloid suppressive cells (MSCs) and regulatory T cells (Tregs) (13). For example, in the mouse mammary adenocarcinoma 4T1 cancer model, which represents a highly aggressive model of human breast carcinoma (4), cancer-produced factors promote the generation of MSCs to impair antitumor immune responses (5). In this model, Tregs play an essential role in lung metastasis, as in their absence, 4T1 cancer cells progressed at the primary site (mammary gland) but could not metastasize. The role of Tregs is to protect metastasizing 4T1 cells from NK cells utilizing β-galactoside binding protein (3). Consistent with a recent report that mice with OVA-induced pulmonary allergy had an enhanced growth of i.v. injected B16 melanoma in the lungs (6), metastasis in 4T1 tumor-bearing mice also require an allergic response in the lungs to mediate production of CCL17 and CCL22 and thereby recruit CCR4+ 4T1 cancer cells and Tregs (3).
Airway hypersensitivity and production of Th2-type chemokines are associated with the expression of TSLP (7, 8), a type 1 cytokine that signals via a receptor consisting of TSLPR and IL-7Rα to activate JAK1, JAK2, STAT5A, and STAT5B (9). It is produced by epithelial cells, keratinocytes, mast cells, and basophils in response to a range of stimuli (10) and affects mouse T cell expansion, survival and differentiation (1113). TSLP is a key factor for initiating allergic responses (11, 12), for example, to ovalbumin in the lungs of mice (12, 14). It promotes Th2 responses acting directly on T cells 12, mast cells (15), and NKT cells (16) or indirectly through the “education” of dendritic cells (DCs) (14, 17). Despite its importance in allergy the role of TSLP in oncogenesis is not known. Here, using two cancer models coupled to inhibiting TSLP expression in tumor cells and Tslpr-deficient mice, we report that TSLP also plays an essential role in tumor progression.
Cells and mice
Female BALB/c and C57BL/6 mice were from the Jackson Laboratory (Bar Harbor, ME) and Tslpr −/− mice were described previously (13). The use of 4T1 cells and the generation their non-metastatic 4T1-PE clones were described elsewhere (3). B16F10, MCF-7 and MDA-MB-231, OVCAR433, 2008, HOSEB and BG1 cells were from American Type Culture Collection. U4ACC1273 and 938 mel were from Dr. Ashani Weeraratna (NIA/NIH). CD4+ T cells were isolated by mouse T cell CD4 Subset Column Kit and separated from CD25+ cells using CD25 Microbead kit (Miltenyi Biotec, Auburn, CA). The generation of BM-derived immature DCs was described elsewhere (18).
In vivo manipulations
Animal care was provided in accord with procedures outlined in the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 86-23, 1985). Experiments were performed using 4–8 weeks old female mice in a pathogen-free environment. Syngeneic mice were s.c. challenged with 4T1 cancer cells or their subsets (1x104 cells, in the 4th mammary gland) or B16F10 melanoma cells (1x105) at day 0. To test the role of T cells and DCs, congenic 1x107splenic and lymph node CD4+ T cells (depleted of Tregs) or 1x106 BM-derived immature DCs were i.v. and s.c. injected, respectively, at days 0 and 5 after tumor challenge, and tumor growth was measured every other day. Mice were culled 28 days after tumor challenge and lungs were analyzed for metastases as previously described (3). In vivo CD4+ T cells were depleted by i.p injecting 400 μg anti-CD4 mAb GK1.5 (NCI-FCRDC, Frederick, MD), or normal rat IgG (Sigma) at days − 4, −1, 3 and 7 relative to tumor challenge. Depletion of CD4+ T cells was > 90%, as assessed 3 days after final treatment in the blood of the treated mice. To deplete TSLP in the lungs, lightly anesthetized with 2,2,2-tribromoethanol (Avertin, Sigma-Aldrich) BALB/c mice, 4T1.2 tumor-bearing or naïve but s.c. injected with CM of 4T1.2 cells mice, were treated with 20 μl of anti-TSLP Ab (Clone 152614, R&D Systems) or control IgG via intranasal route (total of 3 times starting days 2, 7, and 17).
Detection of cytokine expression
Cytokines shown in Table 1 were measured using Bio-Plex cytokine assay array by following manufacturer’s instructions (Bio-Rad). TSLP, IL-5, and IL-13 (eBioScience, San Diego, CA) and IL-10 and TARC/CCL17 (R&D Systems) in the blood (plasma) and broncheoalveolar lavage fluid were measured using ELISA in s.c. injected mammary glands of BALB/c mice with 0.2 ml serum-free tumor conditioned media daily for 4 days and cytokines were measured by ELISA 24 hours after last treatment A separate group of similarly treated mice were used to assess cytokine production by ELISA in CD4+ T cells (isolated as described elsewhere (3)) after two days of stimulation with anti-CD3/CD28 beads (Invitrogen). Immunohistochemistry staining was performed as described (3) using paraffined lung sections of 4T1.2 cells or patients with breast cancer (ETIB, NCI, Bethesda, MD). Anti-mouse TSLP Ab (BAF555, R&D, MN), anti- human TSLP Ab (ab47943, Abcam, Cambridge, MA), biotinylated anti-rabbit IgG (BA1000, Fisher Scientific), and IHS reagents were from Thermo Scientific (Fremont, CA).
Expression of proinflammatory cytokines in the conditioned media of metastatic 4T1 and 4T1.2 cells and their respective non-metastatic clones, 4T1-PE and 4T1-NM, as tested by Bio-Plex cytokine assay (Bio-Rad). Shown, +, low; ++, moderate expression; and (more ...)
Statistical Analysis
Results are presented as the mean of triplicates ± SEM of at least three experiments. Differences were tested using Student’s t test and a 2 sided p-value less than 0.05 was considered statistically significant.
Mouse and human tumors express TSLP
We previously reported that lung metastasis of 4T1 adenocarcinoma growing in the mammary gland requires activation of the lungs, with production ofTARC/CCL17 and MDC/CCL22 (3). To identify cancer-produced factors responsible for the activation, we compared cytokine expression profiles of metastatic 4T1 and 4T1.2 cells with their non-metastatic clones 4T1-PE and 4T1-NM (3). The cells differentially expressed variety of cytokines and chemokines, in particular, metastatic cells secreted a number of chemokines, such as CCL5, CCL17, and CXCL1 (Table 1), previously associated with metastasis of cancer cells (3, 19). Surprisingly, we also found that metastatic cells also produced TSLP (Table 1). In particular, its expression was highest in 4T1.2 cells (Fig.1A and Table 1), a clone of 4T1 cells that was selected for its enhanced lung metastasis (Fig.1B and Ref. (4)). TSLP was also found expressed in various human cancer lines, such as breast cancer MCF-7 and MDA-MB-231 cells and melanoma 938 mel cells (Fig.1C), and in human metastatic breast cancer biopsy (Fig.1D), indicating that this is not solely a mouse cancer cell-associated phenomenon.
(A) Metastatic 4T1 cells and 4T1.2 cells, but not non-metastatic 4T1-PE and 4T1.2-NM cells, express TSLP (mean ± SEM of triplicates, pg/ml). (B) Lung metastasis of metastatic 4T1 and 4T1.2 cells and their non-metastatic clones, 4T1-PE and 4T1.2-NM, (more ...)
Cancer-produced TSLP promotes tumor progression
Although the role of TSLP in cancers is not known, TSLP is mostly shown to be a key factor that initiates Th2-type responses (11, 12). To clarify the abundant expression of TSLP by cancer cells, we hypothesized that TSLP mediate Th2 responses, promoting cancer escape also promoting TH2-type responses. To test this idea, we first tested the ability of shRNA-generated 4T1 cell clones expressing low (clone B7, < 150 ± 15 pg/ml) or moderate levels (clone C7, > 380 ± 30 pg/ml) of TSLP to progress and metastasize after s.c. implantation in the mammary gland of female BALB/C mice. Whereas control mice injected with an irrelevant shRNA-transduced 4T1 cells (K5) or with clone C7 generated large tumors (Fig.2A) and many lung metastases (Fig.2B), a low TSLP producer clone, B7, grew poorly and had few metastases (Fig.2A,B). To rule out potential cell cloning-associated problems, we have also generated additional shRNA-mediated TSLP non-expresser clones in 4T1.2 cells (clens A6 and B5). Unlike control shRNA-transduced K3 clone (Fig.2C,D), the TSLP non-expresser clones A6 and B5 failed to induce tumor growth (Fig.2C) and metastasis (Fig.2D). Since TSLP knock down did not affect in vitro proliferation and viability of any of the clones used (data not shown), these data indicate that cancer cell-produced TSLP is required for cancer progression and metastasis.
Unlike shRNA control K5 clone or C7 clone (high level TSLP expressers) of 4T1 cells or K3 of 4T1.2 cells, a TSLP-low clone B7 of 4T1 cells (A, B) and A6 and B5 clones of 4T1.2 cells (C,D) poorly progressed (A,C) and metastasized (B,D) in BALB/c mice. (more ...)
To confirm this, we challenged congenic TSLP receptor deficient (Tslpr−/−) mice with WT 4T1.2 cancer cells, and found that cancer progression (Fig.3A) and metastasis (Fig.3B) was also significantly decreased in these mice as compared to WT mice. This observation was not restricted to breast cancer cells, as s.c.-injected B16 melanoma progressed significantly slower in congenic Tslpr−/− mice than in WT C57BL/6 mice (Fig.3C). Interestingly, serum levels of TSLP were also positively correlated with tumor growth in WT mice (Fig.3D), further indicating the importance of TSLP in malignant cell growth. Taken together, our data indicate that TSLP promotes cancer progression and metastases though the activation of the host’s responses, as cancers cannot progress when the host is deficient in TSLPR.
Tslpr−/− mice do not efficiently support cancer progression (4T1.2 cells, A, and B16 melanoma, C) and metastasis (4T1.2 cells, B). Serum TSLP levels positively correlate with a cancer burden (R2=0.996, D). Shown are data of individual (more ...)
The importance of CD4+ T cells as targets of cancer-produced TSLP
TSLP is known to induce airway allergic inflammation by activating CD4+ T cells either directly (12) or indirectly through DCs (14, 17), suggesting that cancers may also utilize TSLP to promote cancer progression by targeting CD4+ T cells. To test this idea, non-Treg CD4+ T cells (CD4+CD25 T cells depleted of CD25+ Tregs) and bone marrow-derived DCs isolated from wild type BALB/c mice were adoptively transferred into congenic 4T1 tumor-bearing Tslpr−/− mice. In concordance with the importance of Tregs in metastases (3), the transfer of non-Treg WT CD4+ T cells did not reverse the inability of 4T1 cancer cells to metastasize in Tslpr−/− mice (Fig.4A). However, we detected significantly enhanced primary tumor growth in Tslpr−/− mice transferred with non-Treg WT CD4+ T cells (Fig.4B), suggesting the importance of WT CD4+ cells in cancer progression. Consistent with this, the depletion of CD4+ T cells in 4T1 tumor-bearing WT mice also reduced cancer progression (Fig.4C). To our surprise, the transfer of the WT DCs did not increase and in fact markedly reduced the already poor ability of Tslpr−/− mice to support tumor growth (Fig.4D). As expected, there was no effect when the DCs were added to WT mice (Fig.4D). Since the DC transfer results in Tslpr−/− mice may also indicate the need of having both types of the cells, CD4+ T cells and DCs isolated from WT and Tslpr−/− mice were criss-cross mixed and co-transferred into 4T1 tumor-bearing Tslpr−/− mice. The enhanced cancer progression was only detected in the mice receiving WT CD4+ T cells regardless of DCs used (WT or Tslpr−/, Fig.4E). In contrast and as expected, the co-transfer of CD4+ T cells and DCs from Tslpr−/− mice did not have any effect (Fig.4E) and the transfer of Tslpr−/− CD4+ T cells and WT DCs significantly reduced tumor burden in Tslpr−/− mice (Fig.4E). Thus, taken together and consistent with the importance of CD4+ T cells as a target of TSLP (11, 12), cancer-produced TSLP acts on CD4+ T cells to promote cancer progression. Moreover, supporting our recent report on the importance of Tregs in metastasis (3), transfer of WT DCs did not enhance but significantly abrogated lung metastasis in Tslpr−/− mice (Fig.4F) whether or not CD4+ T cells were co-transferred (data not shown). In control tumor-bearing WT mice, DC transfer did not significantly affect metastasis (Fig.4F). Taken together, these data indicate that TSLP helps to promote tumor progression acting on CD4+ T cells.
Unlike lung metastases (A), the diminished ability of Tslpr−/− mice to support tumor growth was reversed by adoptive transfer of T cells (B). Depletion of CD4+ T cells inhibits 4T1 tumor progression in WT BALB/c mice (C). Compared with (more ...)
Cancer uses TSLP to promote Th2-type immune responses
In allergic responses, TSLP conditions the lung immune environment inducing Th2-type skewed CD4+ T cell responses (20). Interestingly, we have also detected significant expression of TSLP in the lungs (airway lining cells) of 4T1 tumor-bearing mice (Fig.5A), suggesting that cancer also induces TSLP production at distant metastasis sites, presumably enhancing Th2 responses the lungs, presumably to regulate CD4+ T cells. To confirm this, we have s.c. injected the mammary gland of naïve BALB/C mice with conditioned medium (CM) from metastatic TSLP-expresser 4T1 cancer cells (CM-4T1) and TSLP non-expresser cells (CM-4T1PE). As a result, TSLP was present in BAL of untreated mice (Fig.5B), it was significantly enhanced in BAL and blood (plasma) of mice only treated with CM-4T1 cells, but not CM-4T1PE cells (Fig.5B), supporting the possibility that cancer cells produce TSLP to favor a Th2 type response in lung cells and facilitate lung metastasis (20). In support of this hypothesis, the lungs of CM-4T1 treated mice also expressed significantly enhanced Th2-type cytokines, including IL-5, IL-13 (Fig.5B) and IL-10 (Fig.5C) as compared with the lungs of mice injected with TSLP non-expresser CM-4T1PE cells. Importantly, intra nasal delivery of a neutralizing antibody to TSLP, but not control antibody, abrogated the enhanced levels of both TSLP (Fig.5D) and IL-10 (Fig.5C) in the mice treated with CM of TSLP-expresser cells. Moreover, TSLP-expresser CM from 4T1.2 cells also enhanced CCL17 expression in the lungs (Fig.6A), which can promote the recruitment of Tregs to protect metastasizing cells from NK cells in the lungs (3). In support of this, the lungs of mice s.c. injected with TSLP-expressing CM, but not with TSLP-expressing CM from A6 cells, had elevated amounts of FoxP3+Tregs (Fig.6B).
(A) Primary 4T1.2 tumor induces TSLP expression in lung epithelium of BALB/c mice. Shown is a representative lung section stained with anti-TSLP and control antibody of tumor-bearing and naïve mice. Expression of IL-5, IL-13, and TSLP in BAL and (more ...)
Mice s.c. injected with CM-4T1.2 cells express higher levels of CCL17 (A) and have increased amounts of FoxP3+ Tregs (B) in the lungs. Control mice were injected with CM of TSLP non-producer 4T1.2 cells (clone 6, CM-A6). (C) The injection of CM-4T1.2 (more ...)
To explain cancer-promoting role of CD4+ T cells, we hypothesized that cancer used TSLP to induce their Th2 differentiation. Indeed, CD4+ T cells isolated from spleens of BALB/C mice s.c. injected with CM from TSLP-producing 4T1.2 cells secreted significantly higher levels of IL5, IL-10 and IL-13 (Fig.6C) than T cells from mice treated with CM from TSLP non-producer cells (either from non-metastatic cells [data not shown and Fig.5B] or from 4T1.2 cells with shRNA-mediated TSLP knockdown, Fig.6C). Conversely, CD4+ T cells from TSLP non-expresser CM- treated mice expressed much more IFNγ (Fig.6C). Considering an immunoregulatory and cancer escape-promoting role of Th2 cytokines like IL-10 and IL-13 (2123), our data indicate that cancer controls immune-surveillance by producing and utilizing TSLP to induce Th2-type differentiation of CD4+ T cells.
We recently reported that although tumor progression was associated with lung metastasis of 4T1 cancer cells (see also Fig.2,3), they can be dissociated, as the absence of Tregs only abrogated lung metastasis without affecting the growth of a primary tumor in the mammary gland (3). The role of Tregs was to facilitate lung metastasis by protecting metastasizing cells from NK activity (3). Here, we report that tumor progression is promoted by non-Treg Th2 differentiated CD4+ T cells in response to TSLP and that TSLP is abundantly expressed in various cancers, including human carcinomas such as breast cancer and melanoma. Our studies in mice indicate that cancer-produced TSLP can promote cancer escape by inducing Th2 differentiation of CD4+ T cells and Th2-type skewed responses, as in allergic inflammation (7). However, our data indicate that cancer-produced TSLP may also be responsible for the lung metastasis by inducing production of CCL17 in the lungs and thereby recruiting Tregs, a key requirement for a successful lung metastasis of 4T1 cancer cells (3). Besides Tregs (24, 25), CCL17 can also recruit other immune cells with potentially regulatory activities, such as Th2 type CD4+ T cells, NK cells, iNKT cells, and B cells (21, 2628). Moreover, we also detected significant infiltration of Gr1+CD11b+ MSCs in the lungs of mice injected with CM of TSLP-expresser, but not non-expresser, 4T1 cells, which appeared not to require CCL17 (data not shown), suggesting that the induction of other chemokines. Despite the fact that cancer progression can be promoted by all these cells, and specifically by TSLP-activated Tregs (29, 30) or DCs (14, 17), our data indicate that non-Treg subsets of CD4+ T cells are targets of TSLP, whereas DCs did not appear to be critical in this process. Our mechanistic studies indicate that, as in TSLP-mediated allergic responses (7, 8, 20), cancer-produced TSLP induced Th2 differentiation of CD4+ T cells. As a result, we detected significant production of IL-10 and IL-13, cytokines that promote cancer escape by activating NKT cells (21) and MSCs (22, 23); by inducing Th2-type immune responses that suppress anti-tumor Th1 responses and CD8+ CTLs (31), and activating iTregs or generating suppressive Tr1 cells (32, 33). In this process, cancer appears to also use TSLP to initiate a chain of suppressive events by inducing the production of chemokines (that recruit suppressive and other immune cells) as well as the immunomodulatory cytokines IL-10 and IL-13. Taken together, our data indicate that TSLP may serve as a cancer prognostic marker, which may also explain the increased lung metastases reported in asthmatic patients with breast cancer (3, 6). We propose that targeting TSLP may be a way to control cancers, as the inactivation of TSLP in tumors alone or disabling its signaling (as shown by the use of Tslpr−/− mice) was sufficient to diminish both cancer progression and metastasis.
This research was supported by the Intramural Research Programs of the National Institute on Aging and the National Heart, Lung, and Blood Institute, NIH.
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