# Cancer cell-derived sialylated IgG interacting with Siglec-7/9/10 is a potential immunotherapeutic target in pancreatic cancer

## TL;DR

A cancer cell protein called SIA-IgG helps pancreatic tumors avoid the immune system, but blocking it could improve immunotherapy.

## Contribution

SIA-IgG is identified as a novel immunosuppressive factor in pancreatic cancer that interacts with Siglec receptors.

## Key findings

- SIA-IgG is overexpressed in pancreatic cancer and inhibits macrophage activity.
- SIA-IgG and TGF-β1 form a feedback loop to suppress immunity in pancreatic tumors.
- Blocking SIA-IgG reverses immunosuppression and shows therapeutic potential in PDAC.

## Abstract

The limited effectiveness of T cell-based immune checkpoint blockade (ICB) therapy in most patients with pancreatic ductal adenocarcinoma (PDAC) is largely due to poor CD8+ T cell infiltration and a highly immunosuppressive microenvironment driven by excessive myeloid cell accumulation. This highlights the urgent need for new immunotherapy targets and strategies. In this study, an identified pro-cancer factor, cancer cell-derived sialylated IgG (SIA-IgG), is found to be significantly overexpressed in pancreatic cancer cells. SIA-IgG inhibits macrophage phagocytosis and induces an M2-like immunosuppressive phenotype through interactions with Siglec-7/9/10. SIA-IgG and TGF-β1, a key immunosuppressive factor, reinforce each other in a positive feedback loop, promoting immune evasion in PDAC. Blocking SIA-IgG with specific monoclonal antibodies shows significant therapeutic potential through reversal of PDAC’s immunosuppressive microenvironment. Our findings identify the SIA-IgG/Siglec axis as an immunotherapeutic target for PDAC, offering a feasible approach for the development of immunotherapeutic strategies.

•SIA-IgG is highly expressed in PDAC and promotes immune evasion•SIA-IgG functions as a ligand for Siglec-7/9/10 to drive M2 macrophage polarization•A positive feedback loop between SIA-IgG and TGF-β1 amplifies immune suppression•Targeting SIA-IgG remodels the immunosuppressive tumor microenvironment in PDAC

SIA-IgG is highly expressed in PDAC and promotes immune evasion

SIA-IgG functions as a ligand for Siglec-7/9/10 to drive M2 macrophage polarization

A positive feedback loop between SIA-IgG and TGF-β1 amplifies immune suppression

Targeting SIA-IgG remodels the immunosuppressive tumor microenvironment in PDAC

Zhang et al. identify cancer cell-derived sialylated IgG as a driver of macrophage-mediated immune suppression in PDAC. Targeting SIA-IgG remodels the tumor microenvironment and reveals a potential immunotherapeutic strategy.