Galectin-3 Released by Pancreatic Ductal Adenocarcinoma Suppresses γδ T Cell Proliferation but Not Their Cytotoxicity

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment with a dense desmoplastic stroma. The expression of beta-galactoside-binding protein galectin-3 is regarded as an intrinsic tumor escape mechanism for inhibition of tumor-infiltrating T cell function. In this study, we demonstrated that galectin-3 is expressed by PDAC and by gamma delta or alpha beta T cells but is only released in small amounts by either cell population. Interestingly, large amounts of galectin-3 were released during the co-culture of allogeneicin vitroexpanded or allogeneic or autologous resting T cells with PDAC cells. By focusing on the co-culture of tumor cells and gamma delta T cells, we observed that knockdown of galectin-3 in tumor cells identified these cells as the source of secreted galectin-3. Galectin-3 released by tumor cells or addition of physiological concentrations of recombinant galectin-3 did neither further inhibit the impaired gamma delta T cell cytotoxicity against PDAC cells nor did it induce cell death ofin vitroexpanded gamma delta T cells. Initial proliferation of resting peripheral blood and tumor-infiltrating V delta 2-expressing gamma delta T cells was impaired by galectin-3 in a cell-cell-contact dependent manner. The interaction of galectin-3 with alpha 3 beta 1 integrin expressed by V delta 2 gamma delta T cells was involved in the inhibition of gamma delta T cell proliferation. The addition of bispecific antibodies targeting gamma delta T cells to PDAC cells enhanced their cytotoxic activity independent of the galectin-3 release. These results are of high relevance in the context of anin vivoapplication of bispecific antibodies which can enhance cytotoxic activity of gamma delta T cells against tumor cells but probably not their proliferation when galectin-3 is present. In contrast, adoptive transfer ofin vitroexpanded gamma delta T cells together with bispecific antibodies will enhance gamma delta T cell cytotoxicity and overcomes the immunosuppressive function of galectin-3.