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Published on: November 28, 2019
Glycosylated extracellular matrix drives immune suppression by modulating macrophage-T cell crosstalk in
Ludovica Tarantola1, Eleanor J Tyler1, Ying Liu1
1Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, UK.
Abstract:
The tumor extracellular matrix (ECM) is increasingly recognized as a key driver of immune suppression and therapy resistance in cancer. However, the specific ECM components and mechanisms that create this immunosuppressive environment remain poorly understood, hindering the development of new therapies. Here, we use comprehensive multi omics profiling of triple-negative breast cancer (TNBC), an aggressive and treatment-resistant subtype, to investigate this issue. We report that ECM immunomodulation in TNBC is mediated by post-translational glycan modifications on ECM proteins. Using decellularized human TNBC samples, we show that targeted enzymatic removal of these ECM glycans modifies the tumor immune microenvironment. This modification reprograms tumor-associated myeloid cells toward an immunomodulatory phenotype and improves infiltration of T cells. Notably, ECM desialylation alters selectin and selectin-ligand programs on T cells, consistent with improved trafficking and intratumoral access. In parallel, macrophage-T cell interactions are reshaped, leading to reduced T cell exhaustion. Our findings identify ECM glycan modifications as critical regulators of the innate and adaptive TNBC immune microenvironment. They suggest that targeting ECM glycosylation could offer potential strategies to boost anti-tumor immunity in this aggressive breast cancer subtype.
Insights
Tumor extracellular matrix (ECM) glycans suppress anti-cancer immunity. Targeting these ECM glycan modifications in triple-negative breast cancer (TNBC) can reprogram immune cells and enhance T cell infiltration, offering new therapeutic strategies.
Area of Science:
- Cancer Biology
- Immunology
- Glycobiology
Background:
- The tumor extracellular matrix (ECM) significantly influences cancer progression, immune evasion, and therapeutic resistance.
- Understanding the specific ECM components and mechanisms driving immune suppression in aggressive cancers like triple-negative breast cancer (TNBC) is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of ECM glycan modifications in mediating immune suppression within the TNBC tumor microenvironment.
- To explore the potential of targeting ECM glycosylation as a therapeutic strategy to enhance anti-tumor immunity.
Main Methods:
- Comprehensive multi-omics profiling of TNBC samples.
- Utilizing decellularized human TNBC tissues for experimental manipulation.
- Employing targeted enzymatic removal of ECM glycans to assess effects on the tumor immune microenvironment.
Main Results:
- ECM glycan modifications were identified as key mediators of immune suppression in TNBC.
- Enzymatic removal of ECM glycans reprogrammed tumor-associated myeloid cells towards an immunomodulatory phenotype.
- Improved T cell infiltration and reduced T cell exhaustion were observed following ECM glycan modification, alongside altered selectin-ligand interactions.
Conclusions:
- ECM glycan modifications are critical regulators of both innate and adaptive immune responses within the TNBC tumor microenvironment.
- Targeting ECM glycosylation presents a promising therapeutic avenue for enhancing anti-tumor immunity in triple-negative breast cancer.
