193P - Engagement of sialylated glycans with Siglec receptors on suppressive myeloid cells inhibit anti-cancer immunity via CCL2

Background

Overexpression of sialic acids on glycans, called hypersialylation is a common alteration found in cancer. Hypersialylation can, for example, enhance immune evasion via interaction with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we tested the role of sialic acid on myeloid-derived suppressor cells (MDSCs) and their interaction with Siglec receptors.

Methods

Siglec expression of murine and human MDSCs in healthy conditions and tumor setting was assessed by flow cytometry and MALDI-MS analyses. Functional analysis of Siglec-E knockout on MDSCs in mice was evaluated using Siglec-ExLysMCre mice and suppressive capacity was tested in vitro. Results were confirmed in the human setting using an in vitro assay to generate MDSC-like cells including RNA-Sequencing and a MDSC suppression assay with cancer-derived MDSCs.

Results

We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors. In murine cancer models of emergency myelopoiesis, Siglec-E knockout on myeloid cells resulted in prolonged survival and increased infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation led to strong reduction of their suppressive potential. We further identified CCL2 as mediator involved in T cell suppression upon interaction of sialoglycans and Siglec receptors on MDSCs.

Conclusions

Our results provide mechanistic insights how sialylated glycans inhibit anti-cancer immunity by facilitating CCL2 expression.

Legal entity responsible for the study

The authors.

Funding

The authors.

Disclosure

H. Läubli: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Palleon Pharmaceuticals, GlycoEra; Financial Interests, Institutional, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.