Abstract
Thymic stromal lymphopoietin (TSLP) has emerged as an important, but contradictory, player conditioning tumor growth. In certain contexts, by driving T helper (h) 2 responses via tumor-associated OX40 Ligand (OX40L)+ dendritic cells (DCs), TSLP may play a pro-tumorigenic role. The study elucidates the importance of TSPL in pancreatic ductal adenocarcinoma (PDAC), by analyzing: i) TSLP levels in PDAC cell-line supernatants and plasma from patients with locally-advanced/metastatic PDAC, pre- and post-treatment with different chemotherapeutic protocols, in comparison with healthy donors; ii) TSLP and OX40L expression in PDAC and normal pancreatic tissues, by immunohistochemistry; iii) OX40L expression on ex vivo-generated normal DCs in the presence of tumor-derived TSLP, by flow cytometry; iv) clinical relevance in terms of diagnostic and prognostic value and influence on treatment modality and response.Some PDAC cell lines, such as BxPC-3, expressed both TSLP mRNA and protein. Normal DCs, generated ex vivo in the presence of TSLP-rich-cell supernatants, displayed increased expression of OX40L, reduced by the addition of a neutralizing anti-TSLP polyclonal antibody. OX40L+ cells were detected in pancreatic tumor inflammatory infiltrates. Abnormally elevated TSLP levels were detected in situ in tumor cells and, systemically, in locally-advanced/metastatic PDAC patients. Of the chemotherapeutic protocols applied, gemcitabine plus oxaliplatin (GEMOX) significantly increased circulating TSLP levels. Elevated plasma TSLP concentration was associated with shorter overall survival and increased risk of poor outcome. Plasma TSLP measurement successfully discriminated PDAC patients from healthy controls.These data show that TSLP secreted by pancreatic cancer cells may directly impact PDAC biology and patient outcome.
Highlights
Tumor-related inflammation frequently exhibits profiles that promote tumor growth and protect malignant cells from the immune system [1]
To determine whether mRNA expression translates into protein production, Thymic stromal lymphopoietin (TSLP) levels were assessed in the conditioned medium (CM) of the three cell lines by specific ELISA
The cutoff value of 4.76 ng/ml was associated with the highest diagnostic accuracy [p = 0.04, Area Under Curve (AUC) = 0.6129, sensitivity 61%, specificity 60%]. This explorative study found that Pancreatic adenocarcinoma (PDAC) cells themselves, both in vitro and in situ, can elaborate TSLP, a cytokine known to promote type 2 activation/maturation of resident tumor dendritic cell (DC)
Summary
Tumor-related inflammation frequently exhibits profiles that promote tumor growth and protect malignant cells from the immune system [1]. Cancer cells can create a favorable microenvironment by co-opting cells of the innate immune system, such as myeloid-derived suppressor cells, to become components of the pro-tumorigenic stroma [2]. They can avoid the host’s tumor-specific T-cells by skewing the acquired immune response from cytotoxic T helper (h) 1 toward the permissive Th2 phenotype, and/or by inducing immunosuppressive regulatory T cells (Treg) [3]. It was found to be highly expressed outside the thymus, namely by epithelial cells of the lung, intestine and skin, and by fibroblasts, mast cells, and smooth muscle cells [9] It is recognized as a critical mediator involved in the maintenance of Th2type homeostasis at barrier surfaces [10]. This ligand is critical for its ability to polarize naïve T cells into inflammatory Th2 cells, producing Th2-type cytokines like IL-4, IL-5, IL-13, plus Tumor Necrosis Factor (TNF)-α [14]
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