The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9

Abstract

Siglec-9 is a sialic acid binding lectin predominantly expressed on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers resulting in increased sialylation. Thus when MUC1 is expressed on cancer cells it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we show that this cancer-specific MUC1 glycoform could, through the engagement of Siglec-9, educate myeloid cells to release factors associated with tumor microenvironment determination and disease progression. Moreover MUC1-ST induced macrophages to display a TAM-like phenotype with increased expression of PD-L1. MUC1-ST binding to Siglec-9 did not activate SHP-1/2 but surprisingly induced calcium flux leading to MEK-ERK activation. This work defines a critical role for aberrantly glycosylated MUC1 and identifies an activating pathway following Siglec-9 engagement.

Mapping the O‐glycoproteome using site‐specific extraction of O‐linked glycopeptides (EXoO)

“…Therefore, using EXoO allowed detailed mapping of over one hundred sites on VCAN and MUC1. MUC1 has been reported to be an important molecule in many research areas including different cancers, immunity, and immunotherapy (Hanisch, ; Tarp & Clausen, ; Beatson et al , ; Hanson & Hollingsworth, ). The use of EXoO therefore is advantageous to reveal new biological insight regarding mucin‐type glycoproteins.…”

Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells

“…The previous studies have provided evidence that Sia-SAMP/Siglec interactions can inhibit immune cell activation in in vitro models (21)(22)(23)25). The use of bivalent anti-Siglec-9 antibodies (clones 191240 and E10-286) led to an inhibition of T cell activation, which might be due -.…”

“…+ TILs from NSCLC samples activated with anti-CD3/anti-CD28 antibodies expressed significantly higher surface levels of CD25 ( Figure 3A), CD69 ( Figure 3B), and the newly identified activation marker Siglec-5 (Supplemental Figure 4C) compared with similarly actiby engaging inhibitory CD33rSiglecs, such as Siglec-7 and Siglec-9 (21)(22)(23)(24)(25)(26). Engagement of Siglec-7 and Siglec-9 inhibits NK cellmediated tumor cell killing in vitro (22,23).…”

“…Siglec-9 and its murine functional paralog Siglec-E have also been implicated in myeloid cell-mediated cancer progression (21,24). Binding of the cancerassociated sialylated glycoform of MUC1 to Siglec-9 on macrophages can induce a tumor-associated macrophage (TAM) phenotype that can promote cancer progression and immune evasion (25).…”

“…Myeloid cells were more reactive in a mouse model of Siglec-E deficiency, and increased immunosurveillance was observed in these mice (21). Engagement of Siglec-9 on monocytes/macrophages by a cancer-associated, sialylated glycoform of MUC1 showed polarization toward immune-suppressive TAMs with upregulation of PD-L1 (25). Two analyses examined the function of inhibitory Siglec-7 and Siglec-9 in NK cell-mediated tumor cell killing (22,23).…”