Thymic Stromal Lymphopoietin and Cancer Emma Lo Kuan and Steven F. Ziegler J Immunol 2014; 193:4283-4288; ; This information is current as doi: 10.4049/jimmunol.1400864 of September 28, 2021. http://www.jimmunol.org/content/193/9/4283 Downloaded from References This article cites 50 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/193/9/4283.full#ref-list-1

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Thymic Stromal Lymphopoietin and Cancer Emma Lo Kuan and Steven F. Ziegler Originally shown to promote the growth and activation and B cell development and proliferation in vitro and in vivo of B cells, thymic stromal lymphopoietin (TSLP) is now (1, 4, 11). However, the effects were modest, suggesting that the known to have wide-ranging effects on both hematopoi- influence of TSLP on lymphocyte development is redundant. etic and nonhematopoietic cell lineages. These include Analysis of the expression profiles of the two receptor dendritic cells, basophils, mast cells, B cells, epithelial subunits in human cell populations provided important cells, and CD4+,CD8+, and NK T cells. Although insights into the primary biological role of TSLP. The cell TSLP’s role in the promotion of Th2 responses has been population with the highest known coexpression of TSLPR studied extensively in the context of lung- and skin- and IL-7Ra is myeloid dendritic cells (DCs) (5). Confirming the expression data, TSLP treatment of human DCs induced

specific allergic disorders, it is becoming increasingly Downloaded from clear that TSLP may impact multiple disease states several phenotypic changes, including increased survival, up- within multiple organ systems. This review highlights regulation of MHC class II and costimulatory molecules (CD86 and CD40), and production of a variety of chemo- recent advances in the understanding of the surprising kines, most notably the CCR4 ligands CCL17 and CCL22 role of TSLP in the control of a variety of cancers, both (5, 12). Murine bone marrow–derived DCs acquired a similar solid tumors and leukemia, in which the TSLP/TSLP activated phenotype following TSLP stimulation (13). receptor axis was shown to be an important regulator. Little is known about the signaling pathways that are ac- http://www.jimmunol.org/ The Journal of Immunology, 2014, 193: 4283–4288. tivated following engagement of the TSLPR complex. Initial studies in the mouse showed that STAT5 was activated, but in hymic stromal lymphopoietin (TSLP) is a member of the absence of detectable JAK activation (2), making TSLPR the four-helix bundle family and a distant unique among members of the hematopoietic receptor family. T paralog of IL-7 (1). As the name suggests, TSLP was However, two subsequent articles demonstrated robust and first identified as an activity in the supernatants of a mouse sustained activation of JAK-1 and JAK-2 following TSLP thymic stromal cell line that was capable of supporting im- signaling in primary human DCs and primary human and mature B cell proliferation and development (2–4). In addi- mouse CD4+ T cells (5, 14). Surprisingly, unlike IL-7Ra and by guest on September 28, 2021 tion, TSLP could costimulate thymocyte proliferation, gc in IL-7 signaling, which use JAK-1 and JAK-3, the TSLPR suggesting that it acted as a lymphopoietin (1). A TSLP ho- subunit bound and used JAK-2 in concert with IL-7Ra–as- molog was subsequently identified in humans using in silico sociated JAK-1. These findings resolve a long-standing ques- methods (5, 6). Similarly, several groups isolated a TSLP- tion about the mode of TSLP signaling and show that TSLP- binding in both humans and mice (referred to as induced JAK activation precedes the activation of STAT TSLP receptor [TSLPR]), which bound TSLP with low af- . In the human, studies showed that, in addition to finity (7–10). Sequence analysis found that TSLPR was most STAT5, TSLP stimulation activated STAT1, STAT3, STAT4, closely related to the common g-chain (gc) (7). It is now and STAT6, as well as JAK-1 and JAK-2 (15). One possible known that the functional, high-affinity TSLPR complex is explanation for the discrepancy in the data between species is a heterodimer of TSLPR and IL-7Ra (7, 8). Cross-species that the mouse-signaling study primarily used a pre-B cell line, homology for both the cytokine and its receptor is relatively whereas the human studies largely were performed in primary low (∼40% for each), although, as described below, func- DCs. Consistent with this explanation, our laboratory showed tionally they appear to be quite similar. Thus, the role of this that TSLP-treated mouse DCs activate Jak1 and Jak2, as well as cytokine axis is conserved between man and mouse, despite STAT1, STAT3, and STAT5, although only Stat5-deficient a loss of sequence identity. DCs failed to induce TSLP-specific (16). In addition, The similarity of TSLP to IL-7 and the homology of TSLPR studies using nonhematopoietic cells (airway smooth muscle to gc suggested that TSLP may play a role in regulating cells) showed that TSLP signals through Stat3 (17). Taken lymphocyte development and/or function. Indeed, early together, these data demonstrate that TSLP is capable of acti- studies showed that TSLP was capable of influencing both T vating multiple STAT proteins. Whether TSLP uses similar

Immunology Program, Benaroya Research Institute, Seattle, WA 98101 Abbreviations used in this article: B-ALL, B cell acute lymphocytic leukemia; gc, g-chain, DC, dendritic cell; OX40L, OX40 ligand; Ph, Philadelphia ; Received for publication April 7, 2014. Accepted for publication August 9, 2014. TSLP, thymic stromal lymphopoietin; TSLPR, TSLP receptor. This work was supported in part by National Institutes of Health Grants AI68731, AR56113, HL098067, and CA182783. Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 Address correspondence and reprint requests to Dr. Steven F. Ziegler, Immunology Program, Benaroya Research Institute at Virginia Mason, 1201 9th Avenue, Seattle, WA 98101. E-mail address: [email protected]

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400864 4284 BRIEF REVIEWS: TSLP AND CANCER signaling pathways in other cell lineages and how each STAT basophils during Th2 cytokine–associated inflammatory dis- molecule contributes have yet to be elucidated. eases, including promotion of basophil hematopoiesis from As mentioned above, several cell types were shown to re- the bone marrow in an IL-3–independent manner (33). spond to TSLP. Originally, TSLP was isolated and characterized Taken as a whole, the plethora of cell types that can respond as a lymphocyte growth factor (1, 2, 4), and subsequent studies to TSLP demonstrate the important role of this cytokine in showed that it can promote T cell proliferation and differen- orchestrating the initial response to an epithelial insult (Fig. 1). tiation both in vivo and in vitro (18–20). Finally, as will be Although the normal function of TSLP is likely the mainte- detailed below, TSLP responsiveness of CD4 T cells is a critical nance of Th2-type homeostasis at barrier surfaces (14), dys- feature of the challenge phase of allergic inflammation (21, 22). regulated TSLP expression can result in the development of It has now become apparent that a major TSLP-responsive type 2 inflammatory responses leading to allergic disease. cellular subset in both humans and mice is myeloid-derived Recently, a new and unexpected function for TSLP was DCs (5, 13). Coculture of TSLP-activated DCs with naive found for the induction and regulation of a variety of tumors. syngeneic CD4+ T cells led to T cell proliferation but no TSLP was found to both promote and suppress solid tumor differentiation, suggesting a role for TSLP in CD4+ T cell growth, and somatic mutations and chromosomal trans- homeostasis (23). However, when TSLP-stimulated DCs locations in genes encoding members of the TSLPR complex primed CD4+ T cells in an Ag-specific manner (e.g., in an have been found in a subset of pediatric patients with B cell allogeneic culture), the resulting T cells display characteristic acute lymphocytic leukemia (B-ALL). The remainder of this features of Th2-differentiated cells (production of IL-4, IL-5, review discusses that aspect of TSLP biology, along with the Downloaded from IL-13, and TNF-a), with the exception that IL-10 production potential for therapeutic intervention through modulation of was not evident (12). These data suggest that TSLP-activated the TSLP pathway. DCs primed for inflammatory Th2 cell differentiation. In- terestingly, TSLP, in the absence of IL-12, induced OX40 Role for TSLP in growth and metastasis of solid tumors ligand (OX40L) expression on DCs, and OX40–OX40L It was shown that, for many types of cancers, a Th2 response is interactions were critical for the ability of the DCs to drive Th2 dominant over cytotoxicity induced by CD8 T cells and a Th1 http://www.jimmunol.org/ cell differentiation (24). Consistent with a role in regulating response (34). Tumors with this type of phenotype generally Th2 cytokine responses, TSLP-activated DCs also were capable have a worse prognosis relative to tumors in which Th1-type of supporting the maintenance and further polarization of Th2 responses predominate (35, 36). However, the mechanism by effector memory cells (25). TSLP-conditioned DCs also aug- which Th2-biased immune responses are initiated in tumors mented intestinal epithelial cell–mediated IgA2 class switching remains largely unknown. However, two recent studies in through the induction of APRIL (21). Finally, some in vitro humans demonstrated a role for TSLP in promoting a Th2- studies suggested a role for TSLP in the generation of tolero- like environment in the tumor through expression of the

genic DCs that can drive the differentiation of regulatory cytokine in the tumor microenvironment (Fig. 1). In the first by guest on September 28, 2021 T cells (26–28), although other studies indicated that TSLP study, De Monte et al. (36), studying pancreatic cancer in may hinder the production and/or maintenance of FOXP3+ which a GATA3+ Th2 cellular infiltrate is dominant, showed regulatory T cells in vivo in certain disease processes (29). that cancer-associated fibroblasts can produce TSLP. In vitro, Finally, several innate immune cells express TSLPR and supernatants from cancer-associated fibroblasts were capable respond to TSLP. For example, TSLP can enhance cytokine of activating DCs to drive Th2 differentiation. Importantly, production from mast cells, NKT cells, and eosinophils (30– they found that tumors and tumor-draining lymph nodes 32). Recent work highlighted direct effects of TSLP on contained TSLPR+ DCs, whereas nondraining lymph nodes

FIGURE 1. Schematic diagram of TSLP-regulated responses in tumors. (1) Tumor or tumor-associated stromal cells produce TSLP, which promotes the matura- tion of resident DCs through upregulation of costimula- tory molecules, including OX40L. (2) DCs drive the differentiation of Th2 cells through OX40–OX40L interactions. Th2 cells secrete IL-4 and IL-13, leading to the recruitment and activation of myeloid-derived sup- pressor cells (MDSCs) and tumor-associated macrophages (TAM) (3), both of which are capable of effector T cell responses against the tumor (4). TAM also produce factors that promote angiogenesis and matrix remodeling (5), whereas the tumor and associated stromal cells produce chemotactic and survival factors for the TAM (6). Dashed line: proposed differentiation path. The Journal of Immunology 4285 did not (36). Finally, using a completely in vitro system, leads to development of dermatitis and hair follicle–associated TSLP was shown to be released by human cervical carcinoma cysts. Deletion of TSLP signaling in these animals led to overt cells (37). These investigators suggested that this tumor- tumor formation. Unlike the previous study, they showed that derived TSLP can act on TSLPR+ endothelial cells to pro- CD8+ T cells, but not CD4+ T cells, NK cells, B cells, or mote angiogenesis in cervical cancer. These data suggest that DCs, are more important for TSLP suppression of tumor there is cross-talk between hematopoietic cells that infiltrate formation (41). This group also indicated that TSLPR sig- the tumor and stromal elements associated with the tumor that naling may function differently in distinct cell types. A better can promote a microenvironment favorable to the tumor itself. understanding of the complexity of TSLP-responsive cell In the second study, Pedroza-Gonzalez et al. (38) investi- subsets in the context of tumors is clearly required to sort gated the factors that drive a Th2 microenvironment in breast out these data. Another interesting concept in the study by tumors. They demonstrated that TSLP is produced directly Demehri et al. (42) is that the timing and magnitude of TSLP by tumor cells in breast cancer patients. They found that expression are critical. Interestingly, a recent study using the supernatants from explanted tumors were capable of inducing 4T1 transplant breast tumor model showed that transplanted OX40L on DCs in a TSLP-dependent manner and that these TSLPR-deficient mice displayed greater metastasis to the DCs could promote Th2 differentiation of naive CD4 T cells. brain but lesser metastasis to the lung (45). They claimed that In addition, OX40L+ DCs were found in breast tumors. In- this paradoxical result may occur because the blood–brain terestingly, they used a xeno transfer model to show that barrier keeps tumor cells out, but the enhanced systemic Th1 blockade of either TSLP or OX40L could reduce tumor responses that they observed in TSLPR-deficient tumor- Downloaded from growth and IL-13 production (38). Taken together, these two bearing mice may open this gate for tumor cell entry. studies suggest that TSLP is an important player in promoting TSLP, although not detected in normal skin, is expressed in tumor survival through manipulation of the immune response glandular breast epithelial cells in nontumor normal donors. in the tumor itself and that TSLP blockade could be an im- portant therapy for these cancers. TSLPR complex and pediatric B-ALL

The role of TSLP in tumor growth and metastasis is sup- Pediatric acute lymphocytic leukemia is a very heterogeneous http://www.jimmunol.org/ ported by work using an orthotopic model of metastatic breast disease that is associated with a variety of genetic lesions, cancer in the mouse (39). This model uses a cell line (4T1) including recurring chromosomal translocations, deletions, derived from a BALB/c breast ductal carcinoma, which, when and amplifications (46). It is the most common childhood transplanted into a mammary gland, leads to growth of pri- tumor; although 80% of affected children are treated suc- mary tumor with metastases to several organs, including lung cessfully, it remains a leading cause of childhood morbidity (40). This group showed that 4T1 cells produce TSLP and and mortality (47, 48). Recent advances in molecular genetic that the level of TSLP expression is correlated with tumor profiling of B-ALL uncovered the origin of many of these growth and metastasis. They also found that primary tumor genetic abnormalities. They include chromosomal trans- by guest on September 28, 2021 growth was delayed when transplanted into TSLPR-deficient locations (e.g., ETV6-RUNX1, BCR-ABL, and TCF3-PBX1) hosts. Unlike the studies in human tumors, they found that and mutations in genes known to be involved in B cell de- the deficit in these mice was not due to lack of TSLP velopment (e.g., PAX5, EBF1, and IKZF1) (46). The IKZF1 + responses in DCs, but rather it was CD4 T cells that required mutations are especially interesting in that they are a hallmark TSLP responses. Our laboratory found that transplantation of of Philadelphia chromosome (Ph+) B-ALL (with BCR-ABL 4T1 cells into a TSLP-deficient host results in strikingly re- translocations) with poor outcomes; however, they are also 2 duced growth of the primary tumor and a complete inhibition seen in Ph cases that resemble Ph+ patients (referred to as of lung metastasis (E.L. Kuan and S.F. Ziegler, manuscript in Ph-like acute lymphocytic leukemia) (49, 50). These Ph-like preparation). Although the underlying mechanism is not yet cases account for ∼15% of B-ALL, and patients have a higher clear, we found that TSLP can functionally activate mono- risk for relapse compared with Ph+ patients. cytic lineage myeloid-derived suppressor cells and that they Using a variety of methods, several groups simultaneously are lacking in the tumor-bearing TSLP-deficient hosts. found that mutations in the TSLP-signaling pathway corre- In contrast to these studies that suggest a tumor-promoting lated with a significant number of B-ALL cases (Fig. 2). For role for TSLP, two independent groups demonstrated a tumor- example, ∼50% of Ph-like patients had chromosomal rear- suppressing role for TSLP in a murine model of skin cancer rangements involving the TSLPR (also referred to as (41, 42). Both studies used keratinocyte-specific ablation of Notch CRLF2) (51). These rearrangements include deletions that signaling, which was shown to lead to skin barrier defects and join TSLPR and P2RY8 (a gene closely linked to TSLPR)and TSLP-dependent dermatitis (43). Demehri et al. (42) showed that translocations between TSLPR and the IgH locus (51–53). mice with inactivation of Notch signaling through deletion of These alterations lead to increased expression of the TSLPR RBPj in keratinocytes failed to develop skin tumors, even fol- by coupling its expression to the promoter/enhancer of the lowing a chemical carcinogenesis regimen that led to tumor translocation partner. In addition, these translocations were formation in wild-type mice. They found that blocking TSLP seen in ∼60% of acute lymphoblastic leukemia cases in signaling in these mice reduced dermal inflammation and allowed children with (52–54). Interestingly, these fortumorformationandthatinductionofTSLPintheskinof mutations were highly correlated with the presence of JAK2 wild-type mice inhibited tumor formation. Using a variety of mutations and were associated with a poor prognosis (55–57). techniques, they found that TSLP-responsive CD4 T cells were Thus, genetic alterations in TSLPR gene expression are as- both necessary and sufficient for the effects of TSLP in this model. sociated with a form of B-ALL with poor prognosis. Using a similar strategy, De Piazza et al. (41) found that In addition to the chromosomal rearrangements, an acti- induced deletion of Notch1 and Notch2 in keratinocytes vating mutation in the TSLPR gene has been found in Ph-like 4286 BRIEF REVIEWS: TSLP AND CANCER

FIGURE 2. Schematic diagram of TSLPR–IL-7Ra mutations in B-ALL. From left to right, TSLPR (red) and IL-7Ra (gray)–wild-type receptor complex; TSLPR homodimer with F232C mutation; increased TSLPR expression and R683G JAK2 mutation; and IL-7Ra homodimer with S185C mutation.

B-ALL. This mutation changes a phenylalanine residue, in the Mice with systemic overexpression of TSLP may provide a extracellular domain of the TSLPR adjacent to the trans- model for understanding the signaling mechanisms involved. membrane domain, to a cysteine (F232C) (58). This leads to Interestingly, overexpression of TSLP early in the postnatal a gain of function because the resulting TSLPR is able to period was sufficient to drive a B cell lymphoproliferative constitutively homodimerize and signal. Interestingly, a simi- disorder, but administration or induction of TSLP after Downloaded from lar mutation in IL-7Ra, which forms a heterodimer with postnatal day 14 was not, although other studies showed ex- TSLPR to generate a functional TSLPR complex, was found pansion of B cell compartments following TSLP expression in in B-ALL (S185C) (59). In addition, insertions and deletions adult mice (62). Importantly, in these studies the target of within the transmembrane domain of IL-7Ra, all of which TSLP in the bone marrow was late pro-B cells, similar to the resulted in the presence of a de novo cysteine residue, were phenotype seen in pediatric B-ALL (62). One possibility is found in several patients (59). Finally, activating mutation in that the acquisition of mutations targeted to the TSLP-signaling http://www.jimmunol.org/ JAK2 was associated with elevated TSLPR expression in B- pathway leads to an unregulated expansion of this population of ALL (60). These data make a compelling case for enhanced B cell progenitors, allowing for subsequent neoplastic transfor- TSLPR signaling and the development of B-ALL. mation. The development of appropriate animal models is re- The predominant method that has been used to assess the quired to properly test whether this is the case. functional consequences of mutations in TSLPR/CRLF2, IL- 7Ra, and JAK2 is expression in factor-dependent cell lines. Conclusions Retroviral transduction of the mutant genes into the factor- A role for TSLP in type-2 inflammatory responses, especially those at barrier surfaces, is now accepted. In the past 4–5 y, dependent cell line BaF3 showed that their expression ren- by guest on September 28, 2021 dered the cell line growth factor independent (51, 58, 59, 61). a new role for TSLP in tumor immunology has emerged. Although these experiments provided insights into the con- Interestingly, these studies found a rather complicated role for sequences of these mutations on signaling from the receptor, TSLP, with it being tumor promoting in some instances and they did not address the nature of the cells affected in vivo or the tumor inhibiting in others. Furthermore, enhanced activation effect on overall B cell development driven by these mutations. of the TSLP-signaling pathway can lead to neoplastic trans- In an attempt to determine the in vivo function of the formation of B cell progenitors. Therefore, the decision how TSLPR/CRLF2 F232C mutation, bone marrow of wild-type to manipulate TSLP or its signaling pathway is dependent on mice was transduced with retrovirus expressing TSLPR/CRLF2 the tumor type. Defining more specific target(s) underlying with the mutation, followed by transplantation into lethally TSLPR signaling that regulate tumor-suppressive or tumor- irradiated hosts. One animal displayed splenomegaly and indi- promoting functions in different cell types will be important cations of increased myeloproliferation in the blood, as well as to study and is a future direction for cancer therapy. elevated numbers of immature granulocytes and megakaryocytes in the bone marrow (58). Although this study demonstrates that Acknowledgments We thank Michael Stolley for generation of Fig. 2. TSLPR F232C is an activated allele, there are important issues with these studies. First, the investigators stated that the trans- duced bone marrow progenitors did not contribute to the Disclosures lymphoid compartment in an appreciable manner, thus limiting The authors have no financial conflicts of interest. the usefulness of this approach for studying B-ALL. Second, the method used to introduce the mutant receptor allows its ex- References pression in all hematopoietic lineages. This may allow for off- 1. Sims, J. E., D. E. Williams, P. J. Morrissey, K. Garka, D. 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