TSLP drives human tumour progression

Chronic inflammation associated with CD4⁺ T helper 2 (T_H2) cell polarization can promote cancer progression. Two independent studies report that thymic stromal lymphopoietin (TSLP) expression in the tumour microenvironment contributes to tumour growth following intratumoural T_H2 cell differentiation.

TSLP induces inflammatory T_H2 cells — which produce interleukin-13 (IL-13) and tumour necrosis factor (TNF) but no IL-10 — through myeloid dendritic cell (DC) activation. De Monte et al. showed that stimulation of human pancreatic cancer-associated fibroblasts (CAFs) with tumour-derived factors, such as TNF and IL-1β, results in increased secretion of TSLP, whereas Pedroza-Gonzalez et al. report constitutive TSLP production by human breast cancer cells. TSLP-containing supernatant from pancreatic CAFs induced high expression of the TSLP receptor and T_H2-type chemoattractants by myeloid DCs. Moreover, myeloid DCs treated with breast cancer tumour supernatant exhibited an activated phenotype and drove inflammatory T_H2 cell differentiation in an OX40 ligand-dependent manner. Using a TSLP-specific neutralizing antibody, the two groups demonstrated that tumour-derived TSLP directly affects the ability of myeloid DCs to prime inflammatory T_H2 cells.

Interestingly, the phenotype of myeloid DCs that infiltrate pancreatic or breast cancer tumours was found to be similar to that of in vitro TSLP-treated myeloid DCs, suggesting a TSLP-mediated mechanism of inflammatory T_H2 cell differentiation in cancer. This is of physiological relevance, as an increase in the ratio of T_H2 to T_H1 cells in the pancreatic tumour stroma was shown to be associated with disease progression. Furthermore, using humanized mice with breast cancer tumours, Pedroza-Gonzalez et al. demonstrated that the administration of antibodies that neutralize TSLP or its receptor decreases the secretion of T_H2 cell-associated cytokines by tumour-infiltrating T cells and blocks tumour growth.

Thus, these two studies identify a role for TSLP in tumour progression through the activation of a myeloid DC-induced inflammatory T_H2 cell response. Based on their findings, the authors suggest that targeting TSLP or its receptor may be of therapeutic value in the treatment of pancreatic or breast cancer.