Versican associates with tumour immune phenotype and limits T cell trafficking via chondroitin sulfate.

Immunotherapies for cancers of epithelial origin have limited efficacy, and a growing body of evidence links the composition of extracellular matrix (ECM) with the likelihood of a favourable response to treatment. The ECM may be considered an immunological barrier, restricting the localisation of cytotoxic immune cells to stromal areas and inhibiting their contact with tumour cells. Identifying ECM components of this immunological barrier could provide targets that if degraded in situ may support anti-tumour immunity and improve immunotherapy response. Using a library of primary triple negative breast cancer tissues, we correlated CD8+ T cell tumour contact with ECM composition and identified a proteoglycan, versican (VCAN), as a putative member of the immunological barrier. Our analysis reveals that CD8+ T cell contact with tumour associates with the location of VCAN expression, the specific glycovariant of VCAN (defined through the pattern of post-translational attachments of glycosaminoglycans (GAGs)), and the cell types that produce the variant. In functional studies the isomers of chondroitin sulfate presented on VCAN have opposing roles being either supportive or inhibiting of T cell trafficking, and removal of the GAGs ameliorates these effects on T cell trafficking. Overall, we conclude that VCAN can either support or inhibit T cell trafficking within the tumour microenvironment depending on the pattern of GAGs present, and that VCAN is a major component of the ECM immunological barrier that defines the type of response to immunotherapy.