Lung Cancer-Derived Galectin-1 Mediates Dendritic Cell Anergy through Inhibitor of DNA Binding 3/IL-10 Signaling Pathway

Abstract

Lung cancer, one of the leading causes of death worldwide, is often associated with a state of immune suppression, but the molecular and functional basis remains enigmatic. Evidence is provided in this paper supporting the role of lung cancer-derived soluble lectin, galectin-1, as a culprit in dendritic cell (DC) anergy. We have shown that galectin-1 is highly expressed in lung cancer cell lines, together with the serum and surgical samples from lung cancer patients. Functionally, lung cancer-derived galectin-1 has been shown to alter the phenotypes of monocyte-derived DCs (MdDCs) and impair alloreactive T cell response, concomitant with the increase of CD4+CD25+FOXP3+ regulatory T cells. The regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. This effect is inhibited by the addition of lactose, which normalizes the phenotypic and functional alterations seen in MdDCs. Of note, significant upregulation of IL-10 was seen in tumor-infiltrating CD11c+ DCs in human lung cancer samples. This was also noted in mice transplanted with lung cancer cells, but not in those receiving tumor cells with galectin-1 knockdown. Furthermore, a significant reduction was noted in lung cancer incidence and in the levels of IL-10–expressing, tumor-infiltrating DCs, in mice receiving galectin-1–silenced tumor cells. These results thus suggest that the galectin-1/IL-10 functional axis may be crucial in lung cancer-mediated immune suppression, and that galectin-1 may serve as a target in the development of lung cancer immunotherapy.

Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

“…High IL-10 signaling during DC differentiation also could be one of the causes for increased ID3 expression in Wnt5a-DCs, which in turn would account for the higher capacity of Wnt5a-DCs to secrete IL-10. In support of this hypothesis, IL-10 signaling increases ID3 expression, and ID3 overexpression enhanced IL-10 production in CD14 + monocytes, thus establishing a positive feedback in the regulation of these genes (46). In agreement, high ID3 expression is characteristic of TGF-b/IL-4 activated M2 macrophages that express increased levels of IL-10 (47).…”

Lung Cancer-derived Galectin-1 Enhances Tumorigenic Potentiation of Tumor-associated Dendritic Cells by Expressing Heparin-binding EGF-like Growth Factor

“…We have reported that lung cancer-derived galectin-1 causes DCs anergy in cancer microenvironments (16). We further investigated whether galectin-1 is involved in lung cancer-mediated HB-EGF up-regulation.…”

“…We demonstrated previously that lung cancer is capable of modifying the DC phenotype and impair DC function by expressing elevated levels of galectin-1 (16). Galectin-1 has also been implicated in regulating immune responses by controlling T cell survival, cytokine secretion, and transendothelial migration (23)(24)(25).…”

Psoriasis in humans is associated with down‐regulation of galectins in dendritic cells

“…Here, we demonstrate that psoriasis patients have low expression of gal-1 in peripheral blood myeloid DCs and in LCs of lesional and non-lesional skin that together with previous studies in animal models [34] indicate an important role of gal-1 in the immunopathogenesis of psoriasis. The positive role of gal-1 in IL-10 production has been proposed as one of the mechanisms involved in the inhibition of Th1 and Th17 responses [34][35][36] The co-culture experiments showed that galectin inhibition increases IFN-gamma production by CD4+ T cells in response to antigen presentation by DCs, suggesting that galectins also regulate the production of pro-inflammatory cytokines. Interestingly, IFN-gamma production was decreased by addition of recombinant gal-1 to autologous co-cultures of PBLs with moDCs from psoriasis patients.…”