Advances in Bioscience and Biotechnology, 2012, 3, 665-668 ABB Published Online October 2012 (
Thymic stromal lymphopoietin: Next research hotspot of
Tong Wu, Juan Wang, Lihua Jia, Bin Cheng*
Department of Oral Medicine, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
Email: *
Received 2 August 2012; revised 8 September 2012; accepted 19 September 2012
Thymic stromal lymphopoietin (TSLP) is an epithet-
lial cell derived cytokine which has been reported to
be a master regulator in T helper (Th) 2 driven in-
flammation. Through acting on dentritic cells (DCs),
granulocytes, natural killer T cells or directly on
CD4+ T cells, TSLP plays significant roles in the
pathogenesis of atopic diseases consisting of the triad
of asthma, allergic rhinitis and atopic dermatitis. Re-
cently mounting evidence demonstrated that cancer-
related inflammation play decisive roles at different
stages of tumor development, including initiation,
promotion, malignant conversion, invasion, and me-
tastasis. As a crucial regulator of Th2 driven inflam-
mation, the involvement of TSLP in carcinogenesis
have attracted researchers’ attention. However, the
mechanisms of TSLP’s involvement in carcinogenesis
are still largely unknown. In this review we first out-
line the roles of TSLP involved in allergic inflamma-
tion and then we further focus on the recent findings
on TSLP’s tumor promoting activities hoping to pro-
vide hints on elucidation of the TSLP implication in
carcinogenesis in future studies.
Keywords: Thymic Stromal Lymphopoietin;
Inflammation; Cancer; Carcinogenesis
Thymic stromal lymphopoietin (TSLP), an epithelially
derived cytokine initially identified as a bioactive factor
secreted in the supernatants of a murine thymic stromal
cell line in 1994 [1]. TSLP is now known to have im-
pacts on hematopoietic and nonhematopoietic cell in-
cluding B cells, basophils, eosinophils, mast cells, DCs,
CD4, CD8, and NK T cells, and epithelial cells. As a
master regulator of T helper (Th) 2 driven inflammation,
TSLP is capable of activating dendritic cells to promote
T helper (Th) 2 immune responses and directly promote
Th2 differentiation of naïve CD4+ T cell and Th2 cyto-
kine-associated inflammation. [2-6]. TSLP-induced Th2
responses are associated with the pathogenesis of allergic
inammatory diseases, including atopic dermatitis, asth-
ma, and rhinitis. Recently mounting evidence demon-
strated that cancer-related inflammation play decisive
roles at different stages of tumor development, including
initiation, promotion, malignant conversion, invasion,
and metastasis [7-9]. So as a strong mediator in inflame-
mation, the role of TSLP in cancer development has
aroused a great deal of interests [10-12]. However, the
mechanisms of TSLP’s involvement in carcinogenesis
are still largely unknown. In this review we outline the
roles of TSLP involved in allergic inflammation and then
we further focus on the recent finding on TSLP’s tumor
promoting activities.
Thymic stromal lymphopoietin (TSLP), an epithelially
derived cytokine is predominantly expressed by epithet-
lial cells in thymus, lung, skin, intestine and tonsils as
well as stromal cells and mast cells [1,13]. The mouse
TSLP gene is located on chromosome 18, while the hu-
man TSLP gene is located on chromosome 5q22.1 next
to the atopic cytokine cluster on 5q31 [14]. TSLP origin-
nated from both mouse and human exert their biological
activities by binding to a heterodimeric receptor that
consists of the IL-7 receptor α-chain (IL-7Rα) and the
TSLP receptor chain (TSLPR), which has low affinity
for TSLP, but in combination with IL-7Rα generates a
high affinity binding site for TSLP and triggers signaling
[15]. TSLP, which is constitutively expressed in human
thymus, is responsible for the differentiation of T regu-
latory (Treg) cells by modulating the activity of thymic
DCs. In contrast to the restricted expression of TSLP,
TSLPR is more widely detected on many immune cell
types, including dendritic cells (DCs), T cells, B cells,
mast cells, natural killer T cells (NKT) and monocytes as
well as in tissues from heart, skeletal muscle, kidney and
liver which suggests that TSLP can function on a broad
*Corresponding author.
T. Wu et al. / Advances in Bioscience and Biotechnology 3 (2012) 665-668
range of cell types [16]. Although cross-species homol-
ogy for human and mouse TSLP and its receptor is rela-
tively low, both TSLP-TSLPR interactions activate simi-
lar signaling pathways such as the transcription factor
signal transducer and activator of transcription 3 (STAT3)
in human and STAT5 in mouse and human [1].
TSLP has been reported to play a critical role in CD4+ T
cell homeostasis in the peripheral mucosa-associated
lymphoid tissues and in the positive selection and/or ex-
pansion of regulatory T cells in the thymus under normal
physiological conditions [17]. In pathological condition,
TSLP plays significant roles both at the induction phase
of the Th2 response via polarization of DCs to drive Th2
cell differentiation and at the effector phase of the re-
sponse by promoting the expansion of activated T cells
and their secretion of Th2 cytokines [1]. This Th2 skew-
ing properties of TSLP are strongly associated with the
pathogenesis of atopic diseases consisting of the triad of
asthma, allergic rhinitis and atopic dermatitis, which are
characterized Th2 cytokine-dominanted inflammatory.
In skin inflammatory conditions such as atopic derma-
titis, TSLP expression in the epidermis of lesional skin is
higher than that in uninvolved skin or skin of nonallergic
people. Further more the skin-resident DCs in patients
with atopic dermatitis have a more activated phenotype,
which may migrate toward the draining lymph node to
prime CD4+ T cells. TSLP can induce OX40L expres-
sion on DCs, after primed by TSLP-activated DCs via
OX40-OX40L interaction, CD4+ T cells differentiate
into inflammatory Th2 effecter and memory cells, and
thus initiate the adaptive phase of allergic immune re-
sponses [18,19]. In mouse models, only the increasing
TSLP concentrations in the epidermis can induce the
onset of Th2 cytokine-associated inflammation, which
has all the cardinal features of human atopic dermatitis
TSLP has recently been proved to be a key pro-aller-
gic cytokine in chronic airway diseases, such as asthma
and chronic obstructive pulmonary disease (COPD) for
the detection of high levels expression of TSLP in bron-
chial mucosa [21]. The animal experiment demonstrated
that TSLP is both necessary and sufficient for the devel-
opment of Th2 cytokine-associated inflammation of the
airways. Mice expressing a TSLP transgene in the airway
epithelium develop a spontaneous, progressive inflame-
matory disease with all the characteristics of human
asthma, TSLP was capable of activating bone marrow-
derived dendritic cells to upregulate costimulatory mole-
cules and produce the T helper type 2 cell-attracting
chemokine CCL17 [22]. On the contrary, TSLP receptor-
deficient mice failed to develop asthma in response to
inhaled antigen [23].
Recently researches have demonstrated that immune
responses have involved and play a vital role in several
stages of tumor development, such as initiation, promo-
tion, malignant conversion, invasion, and metastasis [7-
9]. As a crucial regulator of Th2 driven inflammation,
the involvement of TSLP in carcinogenesis have at-
tracted researchers’ attention. The available researches
shown that TSLP is associated with several cancer in-
cluding lung, pancreatic and breast cancer [10-12]. How-
ever, the possible regulatory mechanisms of TSLP un-
derlying these cancers are not clear and varied in dif-
ferent tumor.
4.1. Cellular Source and Target of TSLP in
Tumor Microenvironment
Similar to normal skin, lung epithelium, breast epithelial
cells, lung cancer cell and breast cancer cells have the
capacity to express TSLP [10,12]. In contrast with breast
cancer in which TSLP expression is specific to epithelial
cells and no staining can be found in tumor-infiltrating
fibroblasts [12]. One recent research on pancreatic can-
cer demonstrated that cancer-associated fibroblasts
(CAFs) secreted TSLP were an important tumor pro-
moter in cancer progression [11]. These experiments
shown that TSLP expression is up-regulated in pancre-
atic cancer and released by CAFs under the influence of
TNF-α and IL-1β that are secreted by tumor cells. So in
tumor microenvironment, the ability of tumor epithelium
and stroma to secrete TSLP varied according to tumor
content dependent manner. The cellular target of TSLP
include DCs and T cells which induce carcinogenesis
through different mechanisms subsequently [10-12,24].
4.2. TSLP in Lung Cancer
One of the important mechanisms for cancer to escape
immune surveillance is to create an immunosuppressive
microenvironment. It has been reported that Tregs, which
could suppress the activity of lymphocytes and help the
tumor cells to escape the host immune system, were in-
creased in the peripheral blood or tumor microenviron-
ment in patients with cancer [25-28]. In lung cancer, the
prevalence of Tregs in tumor microenvironment was
correlated with the expression of TSLP which was sig-
nificantly increased compared with that in benign lesion
and non-cancer lung tissue and correlated with patho-
logic type, stage, tumor size, and lymph node metastasis
[10]. Further study demonstrated that TSLP was capable
of inducing the differentiation of CD4+ CD25 T cells
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T. Wu et al. / Advances in Bioscience and Biotechnology 3 (2012) 665-668 667
into CD4+ CD25+ Tregs and the subsequent migration
of Tregs to the cancer microenvironment by secreting
chemokines MDC/CCL22 and TARC/CCL17 in a DC-
dependent manner [10].
4.3. TSLP in Pancreatic Cancer
One recent research on pancreatic cancer demonstrated
that TSLP expression is up-regulated in pancreatic can-
cer and released by CAFs under the influence of TNF-α
and IL-1β that are secreted by tumor cells [11]. In vitro
study found that myeloid DCs are activated with features
of TSLP-treated DCs by the supernatant of proinflam-
matory cytokine-treated CAFs and acquire Th2-polariz-
ing capability. In vivo study shown that DCs with of
TSLP-treated and Th2-attracting features are present in
pancreatic cancer patients. Collectively, based on these
available results the authors proposed a hypothesis on
how CAFs secreted TSLP promote Th2-mediated in-
flammation in pancreatic cancer which correlated with
reduced survival in pancreatic cancer under the influence
of tumor cells. Pancreatic tumor cells release proinflam-
matory cytokines (TNF-α and IL-1β) and elicit the secre-
tion of TSLP by CAFs. These CAFs-derived TSLP acti-
vate tumor antigen-load resident DC and induce their
migration to draining lymph nodes where they activate
tumor antigen-specific CD4+ Th2 cells. Finally these
CD4+ Th2 cells home to the tumor under the influence
of tumor-derived Th2 chemoattractants to exert tumor-
promoting effecter functions.
4.4. TSLP in Breast Cancer
Besides pancreatic cancer, breast cancer which were in-
filtrated with tumor promoting inflammatory Th2 cell are
also driven by breast cancer-derived TSLP [12]. TSLP
secreted by breast cancer cells induced OX40L-ex-
pressing DCs migration to the tumor microenvironment
which can smolder type 2 inflammation that perpetuates
breast cancer. Further more, another research in mice on
breast cancer demonstrated that CD4+ T cells are also
targets of cancer-produced TSLP during cancer progress-
sion and metastasis [24]. TSLP was responsible for the
lung metastasis by inducing production of CCL17 in the
lungs and non-Treg subsets of CD4+ T cells, whereas
DCs did not appear to be critical in this process.
The evidence available to date indicates that the cancer-
promoting activity of TSLP from cancer cell or CAFs
varied in different cancers primarily required signaling
through the TSLP receptor on DCs or CD4+ T cells,
promoting Th2-skewed immune responses and produc-
tion of immunosuppressive factors. However, many de-
tails underlying effect of TSLP on cacinogenesis such as
signal transduction mechanisms are largely unknown.
Our previous study found that TSLP was expressed on
mouse oral keratinocyte under inflammation [29], and
TSLP and its receptor were detected on oral squamous
cell carcinoma cell line (unpublished data). Whether
TSLP is also involved in the carcinogenesis in other
epithelial tumor type which progression have been re-
ported to be associated with immune disregulation and
elevated Th2 cytokines expression such as head and neck
carcinoma remains to be fully elucidated in further study
[30,31]. Notably, elucidation of the TSLP implication in
carcinogesesis may offer novel therapeutic options to
complement currently available therapeutic strategies.
This work was supported by grants from the National Natural Science
Foundation of China (No. 91029712) and the Fundamental Research
Funds for the Central Universities of China (2009).
[1] He, R. and Geha, R.S. (2010) Thymic stromal lympho-
poietin. Annals of the New York Academy of Sciences,
1183, 13-24. doi:10.1111/j.1749-6632.2009.05128.x
[2] Ito, T., Wang, Y.H., Duramad, O., et al. (2005) TSLP-
activated dendritic cells induce an inflammatory T helper
type 2 cell response through OX40 ligand. Journal of
Experimental Medicine, 202, 1213-1223.
[3] Lambrecht, B.N. and Hammad, H. (2009) Biology of
lung dendritic cells at the origin of asthma. Immunity, 31,
412-424. doi:10.1016/j.immuni.2009.08.008
[4] Zhang, Y. and Zhou, B. (2012) Functions of thymic stro-
mal lymphopoietin in immunity and disease. Immunology
Research, 52, 211-223. doi:10.1007/s12026-012-8264-z
[5] Roan, F., Bell, B.D., Stoklasek, T.A., Kitajima, M., Han,
H. and Ziegler, S.F. (2012) The multiple facets of thymic
stromal lymphopoietin (TSLP) during allergic inflamma-
tion and beyond. Journal of Leukocyte Biology, 91, 877-
886. doi:10.1189/jlb.1211622
[6] Takai, T. (2012) TSLP expression: Cellular sources, trig-
gers, and regulatory mechanisms. Allergology Interna-
tional, 61, 3-17. doi:10.2332/allergolint.11-RAI-0395
[7] Colotta, F., Allavena, P., Sica, A., et al. (2009) Cancer-
related inflammation, the seventh hallmark of cancer:
Links to genetic instability. Carcinogenesis, 30, 1073-
1081. doi:10.1093/carcin/bgp127
[8] Grivennikov, S.I., Greten, F.R. and Karin, M. (2010)
Immunity, inflammation, and cancer. Cell, 140, 883-899.
[9] Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of
cancer: The next generation. Cell, 144, 646-674.
[10] Li, H., Zhao, H., Yu, J., Su, Y., Cao, S., An, X. and Ren,
Copyright © 2012 SciRes. OPEN ACCESS
T. Wu et al. / Advances in Bioscience and Biotechnology 3 (2012) 665-668
Copyright © 2012 SciRes.
X. (2011) Increased prevalence of regulatory T cells in
the lung cancer microenvironment: A role of thymic stro-
mal lymphopoietin. Cancer Immunology, Immunotherapy,
60, 1587-1596. doi:10.1007/s00262-011-1059-6
[11] De Monte, L., Reni, M., Tassi, E., et al. (2011) Intratu-
mor T helper type 2 cell infiltrate correlates with can-
cer-associated fibroblast thymic stromal lymphopoietin
production and reduced survival in pancreatic cancer.
Journal of Experimental Medicine, 208, 469-478.
[12] Pedroza-Gonzalez, A., Xu, K., Wu, T.C., et al. (2011)
Thymic stromal lymphopoietin fosters human breast tu-
mor growth by promoting type 2 inflammation. Journal
of Experimental Medicine, 208, 479-490.
[13] Friend, S.L., Hosier, S., Nelson, A., et al. (1994) A
thymic stromal cell line supports in vitro development of
surface IgM+ B cells and produces a novel growth factor
affecting B and T lineage cells. Experimental Hema-
tology, 22, 321-328.
[14] Quentmeier, H., Drexler, H.G., Fleckenstein, D., et al.
(2001) Cloning of human thymic stromal lymphopoietin
(TSLP) and signaling mechanisms leading to proliferation.
Leukemia, 15, 1286-1292. doi:10.1038/sj.leu.2402175
[15] Pandey, A., Ozaki, K., Baumann, H., et al. (2000) Cloning
of a receptor subunit required for signaling by thymic
stromal lymphopoietin. Nature Immunology, 1, 59-64.
[16] Ziegler, S.F. and Artis, D. (2010) Sensing the outside
world: TSLP regulates barrier immunity. Nature Immu-
nology, 11, 289-293. doi:10.1038/ni.1852
[17] Watanabe, N., Wang, Y.H,, Lee, H.K., et al. (2005) Has-
sall’s corpuscles instruct dendritic cells to induce CD4+
CD25+ regulatory T cells in human thymus. Nature, 436,
1181-1185. doi:10.1038/nature03886
[18] Wang, Y.H. and Liu, Y.J. (2007) OX40-OX40L interac-
tions: A promising therapeutic target for allergic diseases?
The Journal of Clinical Investigation, 117, 3655-3657.
[19] Liu, Y.J. (2007) Thymic stromal lymphopoietin and
OX40 ligand pathway in the initiation of dendritic cell-
mediated allergic inflammation. Journal of Allergy and
Clinical Immunology, 120, 238-244.
[20] Yoo, J., Omori, M., Gyarmati, D., et al. (2005) Spontan-
eous atopic dermatitis in mice expressing an inducible
thymic stromal lymphopoietin transgene specifically in
the skin. Journal of Experimental Medicine, 202, 541-549.
[21] Redhu, N.S. and Gounni, A.S. (2011) Function and
mechanisms of TSLP/TSLPR complex in asthma and
COPD. Clinical & Experimental Allergy, 42, 994-1005.
[22] Zhou, B., Comeau, M.R., De Smedt, T., et al. (2005)
Thymic stromal lymphopoietin as a key initiator of aller-
gic airway inflammation in mice. Nature Immunology, 6,
1047-1053. doi:10.1038/ni1247
[23] Al-Shami, A., Spolski, R., Kelly, J., et al. (2005) A role
for TSLP in the development of inflammation in an
asthma model. Journal of Experimental Medicine, 202,
829-839. doi:10.1084/jem.20050199
[24] Olkhanud, P.B., Rochman, Y., Bodogai, M., et al. (2011)
Thymic stromal lymphopoietin is a key mediator of breast
cancer progression. Journal of Immunology, 186, 5656-
5662. doi:10.4049/jimmunol.1100463
[25] Ohara, M., Yamaguchi, Y., Matsuura, K., et al. (2009)
Possible involvement of regulatory T cells in tumor onset
and progression in primary breast cancer. Cancer Immu-
nology, Immunotherapy, 58, 441-447.
[26] Li, L., Chao, Q.G., Ping, L.Z., et al. (2009) The preva-
lence of FOXP3+ regulatory T-cells in peripheral blood
of patients with NSCLC. Cancer Biotherapy and Radio-
pharmaceuticals, 24, 357-367.
[27] Tokuno, K., Hazama, S., Yoshino, S., et al. (2009) In-
creased prevalence of regulatory T-cells in the peripheral
blood of patients with gastrointestinal cancer. Anticancer
Research, 29, 1527-1532.
[28] Strauss, L., Bergmann, C., Szczepanski, M., et al. (2007)
A unique subset of CD4+CD25highFoxp3+ T cells se-
creting interleukin-10 and transforming growth factor-
beta1 mediates suppression in the tumor microenviron-
ment. Clinical Cancer Research, 13, 4345-4354.
[29] Wu, T., Jia, L., Du, R., et al. (2011) Genome-wide analy-
sis reveals the active roles of keratinocytes in oral muco-
sal adaptive immune response. Experimental Biology and
Medicine, 236, 832-843. doi:10.1258/ebm.2011.010307
[30] Bose, A., Chakraborty, T., Chakraborty, K., et al. (2008)
Dysregulation in immune functions is reflected in tumor
cell cytotoxicity by peripheral blood mononuclear cells
from head and neck squamous cell carcinoma patients.
Cancer Immunity, 8, 10.
[31] Agarwal, A., Rani, M., Saha, G.K., et al. (2003) Disregu-
lated expression of the Th2 cytokine gene in patients with
intraoral squamous cell carcinoma. Immunological Inves-
tigations, 32, 17-30. doi:10.1081/IMM-120019205
TSLP: Thymic Stromal Lymphopoietin
Th: T Helper
DC: Dentritic Cell
IL-7Rα: IL-7 Receptor α-Chain
TSLPR: TSLP Receptor Chain
Treg: T Regulatory Cell
NKT: Natural Killer T Cells
STAT: Signal Transducer and Activator of Transcription
COPD: Chronic Obstructive Pulmonary Disease
CAF: Cancer-Associated Fibroblast