Abstract:Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine expressed by epithelial cells during allergic inflammation, and activating dendritic cells (DC). Its expression and functional role in cancer remain controversial. We conducted retrospective (n D 89), and prospective studies including patients with untreated primary head and neck squamous cell carcinoma (HNSCC). We found that TSLP was overexpressed by HNSCC tumor cells, and associated with a highly differentiated status. However, no sig… Show more
“…TSLP is an interleukin (IL)-7-like cytokine named '"master switch,"' generally expressed by epithelial cells and capable of promoting a Th2-mediated inflammatory immune response (Guillot-Delost et al,;Liu et al, 2007;Soumelis et al, 2002;Ziegler, 2010). Although marine and human TSLP shows only 43% amino acid identity, it performs similar functions in both species (Liu et al, 2007;Reche et al, 2001).…”
Background
Thymic stromal Lymphopoeitin (TSLP) is a key cytokine involved in inflammation and cancer progression. TSLP gene polymorphisms have been associated with increased susceptibility to cancer progression in different organs. We performed a control case study to examine the correlation of expression and polymorphisms of three nucleotides in TSLP with breast cancer (BC) risk in Saudi Arabian females.
Materials and methods
The study was conducted on 116 healthy control subjects and 127 female patients with BC for the purpose of genotyping. Ten matching tissues provided data on immunohistochemistry to evaluate TSLP expression. Three SNPs (rs10043985, rs2289276, and rs3806933) were genotyped with TaqMan allelic discrimination assay. The patients' ages and estrogen receptor statuses were used to investigate the potential correlations between the different variations of TSLP genotypes and BC risk.
Results
BC tissues expressed positive immuno‐staining for TSLP at a high rate compared to normal matching breast tissues. Malignant breast tumors exhibited higher TSLP expression than benign breast tumors. We also found that the rs3806933 (T) allele frequency decreased the risk of developing BC in the study population (OR = 0.356, p = 0.00027) significantly (0.356 times). Interestingly, statistical analysis revealed that the genotype mutant (AC) and the allele mutant (C) of rs10043985 within TSLP were significantly correlated with an increased BC risk (odds ratio [OR] = 4.762, confidence interval [CI] = 1.000–22.666, p = 0.03244; OR = 4.762, CI = 1.000–22.666, p = 0.03244; and OR = 4.575, CI = 0.975–21.464, p = 0.03516, respectively). In addition, the AC and AC + CC genotypes of TSLP rs10043985 were confirmed to be associated with an increased risk of BC risk in women aged above 48 years, compared with the AA genotype (AC and AC + CC vs. AA: OR = 9.468, CI = 0.493–181.768, p = 0.04537).
Conclusion
The results reveal significant correlation between SNPs in TSLP and BC progression in Saudi Arabian female patients.
“…TSLP is an interleukin (IL)-7-like cytokine named '"master switch,"' generally expressed by epithelial cells and capable of promoting a Th2-mediated inflammatory immune response (Guillot-Delost et al,;Liu et al, 2007;Soumelis et al, 2002;Ziegler, 2010). Although marine and human TSLP shows only 43% amino acid identity, it performs similar functions in both species (Liu et al, 2007;Reche et al, 2001).…”
Background
Thymic stromal Lymphopoeitin (TSLP) is a key cytokine involved in inflammation and cancer progression. TSLP gene polymorphisms have been associated with increased susceptibility to cancer progression in different organs. We performed a control case study to examine the correlation of expression and polymorphisms of three nucleotides in TSLP with breast cancer (BC) risk in Saudi Arabian females.
Materials and methods
The study was conducted on 116 healthy control subjects and 127 female patients with BC for the purpose of genotyping. Ten matching tissues provided data on immunohistochemistry to evaluate TSLP expression. Three SNPs (rs10043985, rs2289276, and rs3806933) were genotyped with TaqMan allelic discrimination assay. The patients' ages and estrogen receptor statuses were used to investigate the potential correlations between the different variations of TSLP genotypes and BC risk.
Results
BC tissues expressed positive immuno‐staining for TSLP at a high rate compared to normal matching breast tissues. Malignant breast tumors exhibited higher TSLP expression than benign breast tumors. We also found that the rs3806933 (T) allele frequency decreased the risk of developing BC in the study population (OR = 0.356, p = 0.00027) significantly (0.356 times). Interestingly, statistical analysis revealed that the genotype mutant (AC) and the allele mutant (C) of rs10043985 within TSLP were significantly correlated with an increased BC risk (odds ratio [OR] = 4.762, confidence interval [CI] = 1.000–22.666, p = 0.03244; OR = 4.762, CI = 1.000–22.666, p = 0.03244; and OR = 4.575, CI = 0.975–21.464, p = 0.03516, respectively). In addition, the AC and AC + CC genotypes of TSLP rs10043985 were confirmed to be associated with an increased risk of BC risk in women aged above 48 years, compared with the AA genotype (AC and AC + CC vs. AA: OR = 9.468, CI = 0.493–181.768, p = 0.04537).
Conclusion
The results reveal significant correlation between SNPs in TSLP and BC progression in Saudi Arabian female patients.
“…Third, TSLP may drive tumour progression in breast- and pancreatic cancer2122 but also manifest tumour protective effects23242526, while genetic rearrangements and mutations in the TSLPR gene ( CRLF2 ) are found in paediatric acute lymphoblastic leukaemia (ALL)27. However, the role of TSLP in cancer is controversial828. Fourth, TSLP was shown to upregulate IL-9 production in vivo to promote Th9 cell-induced allergic inflammation suggesting a possible interplay between the two cytokines and their hallmark Th2 and Th9 responses in allergy29.…”
The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.
“…The potential role of TSLP in cancer development/progression is currently unclear and is still a topic of ongoing investigation. While some studies have provided evidence for a tumor-promoting role 7 , 8 , other studies have shown that TSLP does not play any significant role in tumor progression 9 , 10 . Figure 1 Cartoon representation of the human TSLP:TSLPR:IL-7Rα crystal structure.…”
The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Rα), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP:TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP:alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP:TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-of-principle for use of fragments in the inhibition of TSLP:TSLPR complexation.
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