Figure 3:

Schematic representation demonstrating the co-evolving mechanisms of immune suppression in PC-TME. Immunosuppression is mediated by two exclusive yet inter-dependent mechanisms, which includes: (A) Immune evasion by cancer cells; cancer glycocalyx comprising of the mucins and mucin-associated molecules like galectins sequester the chemokines enhancing its local enrichment near the chemokine receptor on immune cells and result in Treg recruitment, mucin-glycans directly interact with the inhibitory siglecs of T cells and NK cells leading to their impaired function, or chemokines released into the TME by sialic acid residues of glycans decrease DC infiltration. Cumulatively, these phenomena result in an immunosuppressive TME. Additionally, certain mucins like MUC5AC can induce TRAILmediated apoptosis of tumor-infiltrating neutrophils, which further contribute to the immune escape, and (B) CAFs-mediated alterations in immune cell phenotype; CAFs secretome is a rich reservoir of immunosuppressive chemokines like IL-6, LIF, TGF-β, CCL25, CXCL12, CXCL8, which promote the maturation of M2 macrophages, recruitment of MDSCs, and infiltration of Tregs in the tumor milieu, leading to the development of tumor-promoting, immune-suppressive TME. Although no study has yet suggested a direct link between aberrant mucin expression/ glycosylation and TME development, to our understanding, these two events co-evolve and rely on soluble factors like chemokines to fine-tune the mutual co-dependence.