Original Article

Yonago Acta medica 2015;58:137–143

TSLP Expression and High Serum TSLP Level Indicate a Poor Prognosis in Gastric
Cancer Patients
Joji Watanabe,* Hiroaki Saito,* Kozo Miyatani,* Masahide Ikeguchi* and Yoshihisa Umekita†*Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503,
Japan and †Division of Organ Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Yonago
683-8503, Japan

complex. This heterodimer of TSLPR and IL-7R alphais functional and has a high affinity for TSLP.8
CD4+ effector T cells play a central role in initiating
and maintaining antitumor immunological responses.
They are categorized into two subsets based on theircytokine profile. Thus, in mice and humans type 1 (Th1)or type 2 (Th2) have been identified.10, 11 Th1 cells produce interferon-gamma and mainly confer protection
against microbial infections, whereas Th2 cells produce
IL-4, -5, -9, and -13 and help protect against infections
by gastrointestinal nematodes, but they are also responsible for allergic disorders.12, 13 TSLP plays an extremely
important role in the induction of Th2. TSLP-activatedDCs are primed for inflammatory Th2 cell differentiation through their expression of the OX40 ligand.14 Thus,
dysregulated TSLP expression can result in the development of type 2 inflammatory responses leading to allergic disease.
The Th2 response predominates over the Th1 response not only in allergic disease but also in many
types of cancers.15 Tumors associated with a Th2-type
response generally carry a worse prognosis than thosewith a predominantly Th1-type response.16, 17 However,
the mechanism by which Th2-biased immune responses
are initiated in tumors is largely unknown. De Monteet al. recently demonstrated that in pancreatic cancer,
TSLP produced by cancer-associated fibroblasts activates DCs to undergo Th2 differentiation.17 PedrozaGonzalez et al. showed that TSLP produced by breast
cancer cells was capable of inducing OX40 ligand
expression in DCs, which in turn promoted Th2 differentiation by naïve CD4+ T cells.18 These observations

ABSTRACT
BackgroundThymic stromal lymphopoietin (TSLP)
plays an important role in promoting tumor survival, by
manipulating the immune response and angiogenesis.
However, the clinical significance of TSLP in gastriccancer is unclear.
Methods Immunohistochemistry was used to investigate TSLP expression in non-cancerous gastric mucosa
and gastric cancer tissue from patients with gastriccancer. Serum TSLP levels were measured using an
enzyme-linked immunosorbent assay.
Results Tumors with TSLP expression were significantly larger than those without TSLP expression. TSLP
expression was observed more frequently in advanced(T2/T3/T4) than in early (T1) gastric cancer and in stage
3/4 than in stage 1/2. Lymph node metastasis, liver metastasis, positive peritoneal lavage cytology, lymphatic
invasion, and vascular invasion occurred significantly
more often in TSLP-expressing than in non-expressing
tumors. The prognosis of patients with TSLP-positive
tumors was significantly worse than that of patients with
TSLP-negative tumors. Patients with high serum TSLP
concentrations also had a significantly worse prognosis
than those with low concentrations. Multivariate analysis
identified serum TSLP level as an independent prognostic indicator.
Conclusion TSLP is closely related to the progressionof gastric cancer and may predict survival in these patients.
Key words Gastric cancer; Prognosis; TSLP; Tumor

Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7)-like cytokine originally identified by its
ability to promote the proliferation and developmentof immature B cells.1 Several types of cells respond to
TSLP, such as basophils,2 mast cells,3 B cells,4 CD4+,5
CD8+,6 natural killer T cells,7 and dendritic cells (DCs).8
Moreover, a major subset of TSLP-responsive cells identified in both humans8 and mice9 are myeloid-derived
DCs that express high levels of TSLP receptor (TSLPR)

Corresponding author: Joji Watanabewatanabe.j@med.tottori-u.ac.jp
Received 2015 July 3
Accepted 2015 July 15
Abbreviations: CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; DCs, dendritic cells; ELISA, Enzyme-Linked
ImmunoSorbent Assay; IL-7, interleukin-7; Th1, humans type 1
helper T cells; Th2, human type 2 helper T cells; Tregs, regulatory
T cells; TSLP, Thymic Stromal Lymphopoietin; TSLPR, Thymic
Stromal Lymphopoietin receptor

137

J. Watanabe et al.

Measurement of serum TSLP level

suggest an important role for TSLP in promoting Th2biased immune responses in the tumor microenvironment. Indeed, TSLP expression has been confirmed inseveral types of cancer, including breast cancer,19, 20 cervical cancer,21 lung cancer,22 and leukemia,23, 24 and isassociated with the progression and metastasis of thesetumors.19–21
Gastric cancer is one of the most common cancers inAsia and ranks second among all cancer deaths worldwide.25 Helicobacter pylori infection promotes TSLP
production by gastric epithelial cells and induces DCmediated inflammatory Th2-type responses,26 whichhave been shown to predominate in gastric cancer.27
Since H. pylori infection is closely related to the oncogenesis of gastric cancer, we hypothesized that TSLP
expression similarly correlates with tumor progression
and prognosis in these patients. Therefore, in this study
the clinical significance of TSLP expression in patientswith gastric cancer was determined by comparing their
non-cancerous gastric mucosa and gastric cancer tissue
and by measuring serum TSLP concentrations.

Serum TSLP levels were measured in an ELISA using ahuman TSLP immunoassay (DY1398, R&D SYSTEMS,
Minneapolis, MN). All samples were measured in duplicate and the mean concentration was calculated.
Statistical analysis
Associations among factors were evaluated using theχ2 test. Mann-Whitney U-tests were used to determine
statistical differences between groups. Five-year survival
rates were calculated according to the Kaplan-Meiermethod and differences between survival curves were
examined with the log-rank test. Survival data represent
cancer-specific survival. Thus, patients who died fromcauses other than gastric cancer were considered lost tofollow-up as of the time of death. Multivariate analysis
was performed using the Cox proportional hazards model. The accepted level of significance was defined as a Pvalue < 0.05. Statistical analyses were performed using
SPSS Statistics 22.0 for Windows (IBM, Armonk, NY).
RESULTS

MATERIALS AND METHODSTSLP expression in the tissue of non-cancerous
gastric mucosa and gastric cancer

Patients

One hundred and thirty-two and 110 patients whotreated at Tottori University Hospital and pathologicallydiagnosed with gastric cancer were enrolled for immunohistochemistry and Enzyme-Linked ImmunoSorbent
Assay (ELISA), respectively, in the current study. Noneof the patients had received radiotherapy, chemotherapy,
or other medical interventions before surgery. The clinicopathological findings were determined according to
the Japanese Classification of Gastric Carcinoma.28 This
study was approved by the Ethical Committee of the
Tottori University Hospital (approval number: 2573) andwritten informed consent was obtained from all patients.

The immunohistochemically demonstrated expression of
TSLP in non-cancerous gastric tissue and cancer tissue
is shown in Fig. 1. TSLP expression was observed in thecytoplasm of cells from non-cancerous gastric mucosa
obtained from 23 patients (20.9%) and in the cancer tissues of 57 patients (51.8%). There was no significant correlation between the clinicopathological characteristicsof the patients and TSLP expression in non-cancerous
gastric mucosa (Table 1). However, TSLP expression in
the malignant tissue was associated with significantly
larger tumors and occurred more frequently in advanced(T2/T3/T4) than in early (T1) gastric cancer and in stage
3/4 than in stage 1/2 disease. Lymph node metastasis,
liver metastasis, positive peritoneal lavage cytology,
lymphatic invasion, and vascular invasion also occurredsignificantly more often in patients with TSLP-expressing cancer tissue (Table 1).
The 5-year survival rates of patients with TSLP-positive
tumors and TSLP-negative tumors were 21.8% and76.9%, respectively (P = 0.0011; Fig. 2). By contrast,
there was no significant difference in the prognosis ofpatients with TSLP-positive and TSLP-negative noncancerous mucosa (P = 0.4; data not shown).

Immunostaining analysis

Serial sections (4 µm thick) were dewaxed in xylene,
dehydrated in ethanol, placed in citrate buffer pH 6,
and heated in a microwave oven (700 W) for 15 min to
retrieve the antigens. The tissues were then incubated in
3% hydrogen peroxide in methanol to block endogenous
peroxide. Immunohistochemical staining for TSLP was
performed using anti-human TSLP antibody (ab47943;
Abcam, Cambridge, MA) at a dilution of 1:100 and asecondary antibody (ab97080; Abcam) at a dilution of
1:200, according to the manufacturer’s instructions. The
tissue sections were evaluated by a pathologist blinded
to the clinical data and considered positive when > 10%of the cells expressed TSLP.
138

TSLP in gastric cancer

(a)

(b)

(c)

Fig. 1. TSLP expression in non-cancerous gastric mucosa and gastric cancer tissue. (a) Non-cancerous gastric mucosa, × 400; (b) tubular
adenocarcinoma, ×400; (c) poorly differentiated adenocarcinoma, × 400.
Table 1. TSLP expression in gastric cancer and the clinicopathological characteristics of the patients
TSLP expression
Non-cancerous gastric mucosa
Cancer tissue
P-valueP-value
Negative
Positive
Negative
Positive
Tumor size (mm)48.8 ± 31.7
Age (years)
68.5 ± 10.2
Male42
Female11
Histology
Differentiated30
Undifferentiated23
Depth of invasion
T1
27
T2/T3/T4
26
Lymph node metastasis
Absent34
Present
19
Peritoneal metastasis
P0
50
P1
3
Liver metastasis
H0
49
H1
4
Cytology
CY0
31
CY1
5
Lymphatic invasion
Absent20
Present
33
Vascular invasion
Absent24
Present
29
Disease stage
1/2
37
3/4
16

44.0 ± 29.5
64.8 ± 13.3
34
23

0.430
0.108
0.026

42.8 ± 28.3
65.8 ± 12.4
63
24

59.5 ± 34.3
69.4 ± 9.6
14
9

0.023
0.195
0.283

27
30

0.333

41
46

16
7

0.055

29
28

0.994

52
35

4
19

< 0.001

32
25

0.391

59
28

7
16

0.001

50
7

0.227

82
5

19
4

0.070

55
2

0.351

87
0

17
6

< 0.001

36
4

0.600

55
5

11
5

0.016

23
34

0.779

41
46

2
21

0.001

29
28

0.557

49
38

4
19

0.001

41
16

0.807

68
19

10
13

0.001

TSLP, Thymic Stromal Lymphopoietin.

139Percent survival

J. Watanabe et al.
Table 3. Association of prognostic factors with disease-specific survival in patients with gastric cancer,
as determined by the Cox proportional hazards model
Hazard 95% CI
P-value
Prognostic factors
ratio

100

TSLP negative (n = 87 ; 76.9%)

50

0

TSLP positive (n = 23 ; 21.8%)

P = 0.0011
1

2

3

4

5

Years after operation
Fig. 2. Survival curves of gastric cancer patients according to
TSLP expression in gastric cancer tissue.
TSLP, Thymic Stromal Lymphopoietin.

0.972–1.102 0.280
0.105–1.874 0.269
0.395–4.761 0.619
0.861–7.666 0.091
0.494–2.118 0.951
0.131–37.286 0.581
0.763–4.677 0.169
0.524–1.993 0.948
0.990–1.030 0.342
1.000–1.002 0.003*Continuous variable.
†Differentiated, papillary or tubular adenocarcinoma; undifferentiated, poorly differentiated or mucinous adenocarcinoma, or
signet-ring cell carcinoma.
‡T3, penetrating the serosa; T4, invading adjacent organs.
§n0–n3, grade of lymph node metastasis.
||Lymphatic invasion: ly0–ly3, grade of lymphatic vessel invasion¶Vascular invasion: v0–v3, grade of vascular invasion.
CI, confidence interval; TSLP, Thymic Stromal Lymphopoietin.

Table 2. Serum concentration of TSLP in gastriccancer patients and their clinicopathologic
characteristicsn
TSLP (pg/mL) ± SD P-value
0.741

0.576

0.683

Percent survival

Male
92
226.6 ± 583.8
Female40
189.4 ± 614.5
Tumor size (mm)> 40
48233.4 ± 705.3< 40
66
170.5 ± 493.3
Histology
Differentiated67
194.5 ± 580.0
Undifferentiated65236.8 ± 606.2
Depth of invasion
T1
67
165.3 ± 494.9
T2/T3/T4
60
272.6 ± 695.3
Lymph node metastasis
Absent86
226.8 ± 652.5
Present
46
193.9 ± 460.9
Lymphatic invasion
Absent53
133.1 ± 471.8
Present
66
242.5 ± 652.8
Venous invasion
Absent67
133.7 ± 447.2
Present
52
271.2 ± 712.2
Peritoneal metastasis
P0120
192.3 ± 577.3
P1
9486.6 ± 770.3
Liver metastasis
H0126
169.7 ± 544.9
H1
61173.6 ± 761.8
Peritoneal lavage cytology
CY074
172.1 ± 633.7
CY1
9650.6 ± 870.8
Disease stage
1/2
93
182.5 ± 587.5
3/4
39
293.7 ± 600.3
TSLP, Thymic Stromal Lymphopoietin.

Age*
1.035
Sex
0.444
Histology†
1.372
Depth of invasion(T1–T4) ‡2.569
Lymph node metastasis (n0–n3) § 1.023
Peritoneal metastasis (P0–P1)
2.214
Lymphathic invasion (ly0–ly3) || 1.889
Vascular invasion (v0–v3) ¶1.022
Tumor size*
1.010
TSLP concentration
1.001

0.315

0.762

0.308

100

Serum TSLP low (n = 112 ; 75.1%)

500Serum TSLP high (n = 20 ; 54.5%)

P = 0.023
1

2

3

4

5

Years after operation

0.200

Fig. 3. Survival curves of gastric cancer patients according totheir serum TSLP concentrations.
TSLP, Thymic Stromal Lymphopoietin.

0.152

Serum concentration of TSLP in gastric cancer
patients< 0.001

The serum concentration of TSLP was significantly
higher in patients with than in those without liver metastasis (P < 0.001; Table 2) and in patients with than without intraperitoneal free cancer cells (P = 0.043; Table 2).
The serum TSLP concentrations in patients with TSLPpositive and TSLP-negative tumors were 178.2 ± 68.1
and 155.0 ± 122.2 pg/mL, respectively; the difference

0.043

0.326

140

TSLP in gastric cancer

Tregs.32–34 Kim et al. demonstrated that a higher intratumoral Tregs/helper T cells ratio was significantly related
to poor prognosis in gastric cancer patients.35 Further
investigations are needed to clarify the role of TSLP in
the progression of gastric cancer.
An analysis of the relationship between the serum
concentration of TSLP and the prognosis of gastric cancer patients showed that patients with high serum TSLP
concentrations had a significantly worse prognosis thanlow concentrations. The role of serum TSLP level as
an independent indicator of prognosis in gastric cancer
patients was confirmed in a multivariate analysis. Thus,
the measurement of serum TSLP in patients with noninvasive gastric tumors may provide important prognostic information. However, the serum TSLP level was
not related to the serum levels of two important tumor
markers in gastric cancer, CEA and CA19-9. Therefore,
measurement of the serum TSLP level may be useful topredict the prognosis of gastric cancer patients regardless of their serum CEA and CA19-9 concentrations.
To the best of our knowledge, ours is the first study
to show a correlation between serum TSLP level andprognosis in gastric cancer patients. The absence of a
relationship between TSLP expression in non-cancerous
gastric mucosa, gastric cancer tissue, and the concentration of serum TSLP contrasts with the high serum
TSLP concentrations in patients with liver metastasis
and peritoneal lavage cytology. These observations suggest that TSLP is produced by tumor cells, fibroblasts,
and epithelial cells at the metastatic site. In other words,
TSLP expression reflects only a local progression of cancer, and serum TSLP reflects a systemic progression ofcancer, such as metastasis and positive peritoneal lavage
cytology. Because of this, we considered serum TSLP
was only a prognostic indicator. The origin of the highconcentration of serum TSLP remains to be determined.
There is currently no effective treatment for recurrent gastric cancer. Novel strategies for inhibiting tumor
growth and thereby improving survival include theblockage of TSLP or OX40 ligand and thus IL-13 production, an approach recently evaluated in a xeno transfer model.36 However, the close relationship between
TSLP and the progression of gastric cancer suggests that
TSLP is a potentially important and effective target for
the treatment of gastric cancer. Measurement of serum
TSLP levels might improve survival predictions for patients with gastric cancer.

was not statistically significant (P = 0.39). Serum TSLP
concentrations were 130.8 ± 54.1 and 217.5 ± 107.4 pg/
mL in patients with TSLP-positive and TSLP-negative
non-cancerous tissue, respectively; again, the difference
was not statistically significant (P = 0.14).
Based on a mean serum TSLP concentration in our gastric cancer patients of 215.3 pg/mL, a cut-off value of
200 pg/mL was used in this study to determine survival
as a function of TSLP expression. The 5-year survival
rates of patients with high (> 200 pg/mL) and low (≤200 pg/mL) serum TSLP levels were 54.5% and 75.1%,
respectively (Fig. 3). The patients with high serum TSLP
concentrations also had a significantly worse prognosis
than those with low concentrations (P = 0.023; Fig. 3). Ina multivariate analysis, serum TSLP level was an independent prognostic indicator (P = 0.003; Table 3).
Finally, we examined the correlation between the serum
TSLP level and serum carcinoembryonic antigen (CEA)
and carbohydrate antigen (CA) 19-9 levels. The latterare the most frequently used tumor markers in gastriccancer; however, there were no significant correlations
between CEA, CA19-9, and TSLP expression (P = 0.96,
P = 0.55, respectively; data not shown).
DISCUSSIONTSLP expression in both the non-cancerous gastric mucosa and the cancer tissue of our patients with gastriccancer was demonstrated using immunohistochemistry.
TSLP expression in gastric cancer tissue, but not in
non-cancerous gastric mucosa, was found to correlatesignificantly with cancer progression. Furthermore, patients with TSLP-positive had slightly worse prognosis
than those with TSLP-negative, but the reason for thisrelationship is as yet unknown. However, TSLP plays avery important role in the induction of the Th2-based
immune response and previous studies have shown that
the Th1/Th2 ratio is a prognostic indicator in gastriccancer patients.27 In addition, the polarization of group
2 innate lymphoid cells, which produce large amountsof Th2 cytokines, contributes to the immunosuppressive
microenvironment in gastric cancer.29 In cervical cancer,
tumor-derived TSLP also act on TSLPR+ endothelial
cells to promote angiogenesis.21, 30 Neo-angiogenesis isa critical process in cancer progression. In gastric cancer
patients, high microvessel counts correlate significantlywith a poor prognosis.31 Therefore, the TSLP-mediatedincrease in microvessels supplying the malignant tissue of gastric cancer may explain the relation between
TSLP and a poor prognosis. Alternatively, regulatory T
cells (Tregs) may play a role, based on in vitro studies
demonstrating the involvement of TSLP in the generation of tolerogenic DCs that drive the differentiation of

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