Novel immune regulatory circuits in pancreatic cancer
In this thesis, we uncovered th e impact of glycosylation in PDAC tumors in driving the immunosuppres sive TME. We investigated the glycosylation profile of PDAC tumors an d its stroma, and how specific glycan patterns were involved in tumor -stromal-immune crosstalk. To identify clinically relevant glycan-med iated regulatory circuits, we first comprehensively mapped the aberra nt glycosylation profiles in clinical samples of PDAC using transcrip tomic analysis. This work revealed the upregulation of O-glycosylatio n, fucosylation and sialylation genes, as well as the upregulation of several galectins and mucins in tumors (Chapter 2 & 3). In addit ion, the PDAC stroma, a defining characteristic of PDAC that contribu tes to its aggressiveness and therapy resistance, also exhibited upre gulated sialylated glycans (chapter 5). Both tumor- and stroma-associ ated sialylated glycans are sensed by Siglec receptors (Siglec-7/9 an d Siglec-7/9/10/15, respectively), expressed on myeloid cells in the PDAC TME, and their interaction regulates myeloid cell functioning (C hapter 3 & 5). Furthermore, tumor-derived sialic acids drive T ce ll exclusion in the PDAC TME in vivo, and form a barrier for immunoth erapy efficacy (Chapter 4). Thus, sialic acid – Siglec interactions control crosstalk with immune cells, driving myeloid cells to a prot umorigenic phenotype, hampering T cell influx, thereby contributing t o immunotherapy resistance in PDAC (Chapter 3-6).
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DESCRIPTION: In this thesis, we uncovered the impact of glycosylation in PDAC tumors in driving the immunosuppressive TME. We investigated the glycosylation profile of PDAC tumors and its stroma, and how spec ific glycan patterns were involved in tumor-stromal-immune crosstalk. To identify clinically relevant glycan-mediated regulatory circuits, we first comprehensively mapped the aberrant glycosylation profiles in clinical samples of PDAC using transcriptomic analysis. This work revealed the upregulation of O-glycosylation, fucosylation and sialyl ation genes, as well as the upregulation of several galectins and muc ins in tumors (Chapter 2 & 3). In addition, the PDAC stroma, a de fining characteristic of PDAC that contributes to its aggressiveness and therapy resistance, also exhibited upregulated sialylated glycans (chapter 5). Both tumor- and stroma-associated sialylated glycans ar e sensed by Siglec receptors (Siglec-7/9 and Siglec-7/9/10/15, respec tively), expressed on myeloid cells in the PDAC TME, and their intera ction regulates myeloid cell functioning (Chapter 3 & 5). Further more, tumor-derived sialic acids drive T cell exclusion in the PDAC T ME in vivo, and form a barrier for immunotherapy efficacy (Chapter 4) . Thus, sialic acid – Siglec interactions control crosstalk with im mune cells, driving myeloid cells to a protumorigenic phenotype, hamp ering T cell influx, thereby contributing to immunotherapy resistance in PDAC (Chapter 3-6). More information on the thesis Novel immune regulatory circuits in pancreatic cancer END:VEVENT END:VCALENDAR