Unravelling the tumor glyco-code
Authors:   , Rodriguez Camejo Juan Ernesto 
Published: May 2023

Changes in glycosylation are a universal characteristic of malignant transformation, and tumor-specific glycan structures (which we denominate as the tumor glyco-code) are strongly associated with cancer progression and immune-modulation. Because immune cells express a large variety of glycan-binding receptors (called lectins), they can sense and respond to changes in the glycan signature of their environment; which often leads to the induction of inhibitory immune processes in those cells (Chapter I).
In this thesis, we focus in the study of the tumor glyco-code of pancreatic ductal adenocarcinoma (PDAC) that represents one of the most aggressive malignancies, with a 5-year survival rate of only 9%. By analyzing publicly available transcriptomic data of patient samples, we studied two specific glycosylation signatures that correlate with progression, clinical outcome, and the modulation of the immune system: Fucosylation (Chapter II) and Sialylation (Chapter IV).
In Chapter II, we identified that the presence of fucose-containing structures in cancer cells are associated with differences in their epithelial-to-mesenchymal transition status, the clinical outcome of patients and previously published molecular subtypes of PDAC. Moreover, these fucosylated structures can serve as ligands for the receptor DC-SIGN, present in tumour-associated macrophages (TAMs), and modulate their activation by inducing the overexpression of the anti-inflammatory cytokine IL-10.
On the other hand, one of the glycan moieties generally overexpressed in cancer are sialic acids, which can modulate the function of immune cells via interaction with Siglec receptors (Chapter III). We identified that sialylation is increased in PDAC and can induce the differentiation of infiltrating monocytes towards TAMs with an immune modulatory phenotype (Chapter IV). In mice models, we indeed found that TAMs negatively influence immunotherapy while presence of dendritic cells in the tumor microenvironment had a positive impact (Chapter V). Given that sialylated structures can promote tolerogenic myeloid cells, they can lead to resistance to immunotherapy. This work highlights a critical role for sialylated glycans in controlling immune suppression by influencing monocyte differentiation to TAM and provides new potential targets for cancer immunotherapy in PDAC.
Given the presence of a glycan-immune axis that may contribute to PDAC progression, it is important to know the landscape of immune cells present in patients and their expression of lectin receptors. In Chapter VI, we characterized the immune cell populations in peripheral blood of patients with PDAC using mass cytometry by time of flight (CyTOF) with two extensive panels.
Finally, in Chapter VII, we performed a transcriptomic analysis to study the expression of glycosylation-related genes in a pan-cancer setting. We identified genes and pathways specifically associated with different tumor types, characterized the contribution of cancer, immune and stromal cells to the overall glycosylation profile found in tissue, and study the correlation with the clinical outcome of patients.