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 glycosylation profile of PDAC tumors and its stroma, and how specific 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 sialylation genes, as well as the upregulation of several galectins and mucins in tumors (Chapter 2 & 3). In addition, the PDAC stroma, a defining 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 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 functioning (Chapter 3 & 5). Furthermore, tumor-derived 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, driving myeloid cells to a protumorigenic phenotype, hampering T cell influx, thereby contributing to immunotherapy resistance in PDAC (Chapter 3-6).
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