Novel immune regulat ory circuits in pancreatic cancer
In this thesis, we uncov ered the impact of glycosylation in PDAC tumors in driving the immuno suppressive TME. We investigated the glycosylation profile of PDAC tu mors and its stroma, and how specific glycan patterns were involved i n tumor-stromal-immune crosstalk. To identify clinically relevant gly can-mediated regulatory circuits, we first comprehensively mapped the aberrant glycosylation profiles in clinical samples of PDAC using tr anscriptomic analysis. This work revealed the upregulation of O-glyco sylation, fucosylation and sialylation genes, as well as the upregula tion of several galectins and mucins in tumors (Chapter 2 & 3). I n addition, the PDAC stroma, a defining characteristic of PDAC that c ontributes to its aggressiveness and therapy resistance, also exhibit ed upregulated sialylated glycans (chapter 5). Both tumor- and stroma -associated sialylated glycans are sensed by Siglec receptors (Siglec -7/9 and Siglec-7/9/10/15, respectively), expressed on myeloid cells in the PDAC TME, and their interaction regulates myeloid cell functio ning (Chapter 3 & 5). Furthermore, tumor-derived sialic acids dri ve T cell exclusion in the PDAC TME in vivo, and form a barrier for i mmunotherapy efficacy (Chapter 4). Thus, sialic acid – Siglec inter actions control crosstalk with immune cells, driving myeloid cells to a protumorigenic phenotype, hampering T cell influx, thereby contrib uting to immunotherapy resistance in PDAC (Chapter 3-6).
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DESCRIPTION: Novel immune regulatory circuits in pancreatic cancer In this thesis, we uncovered the impact of glycosylation in PDAC tumors in driving the immunosuppressive TME. We investigated the glycosylati on profile of PDAC tumors and its stroma, and how specific glycan pat terns were involved in tumor-stromal-immune crosstalk. To identify cl inically relevant glycan-mediated regulatory circuits, we first compr ehensively mapped the aberrant glycosylation profiles in clinical sam ples of PDAC using transcriptomic analysis. This work revealed the up regulation of O-glycosylation, fucosylation and sialylation genes, as well as the upregulation of several galectins and mucins in tumors ( Chapter 2 & 3). In addition, the PDAC stroma, a defining characte ristic of PDAC that contributes to its aggressiveness and therapy res istance, also exhibited upregulated sialylated glycans (chapter 5). B oth tumor- and stroma-associated sialylated glycans are sensed by Sig lec receptors (Siglec-7/9 and Siglec-7/9/10/15, respectively), expres sed on myeloid cells in the PDAC TME, and their interaction regulates myeloid cell functioning (Chapter 3 & 5). Furthermore, tumor-der ived sialic acids drive T cell exclusion in the PDAC TME in vivo, and form a barrier for immunotherapy efficacy (Chapter 4). Thus, sialic acid – Siglec interactions control crosstalk with immune cells, dri ving myeloid cells to a protumorigenic phenotype, hampering T cell in flux, thereby contributing to immunotherapy resistance in PDAC (Chapt er 3-6).More information on the thesis END:VEVENT END:VCALENDAR