Immune chaperone modulates dendritic cell functions in the tumor microenvironment

Dendritic cells (DCs) are central regulators of the adaptive immune response, thereupon necessary for T cell-mediated cancer immunity. To improve anti-tumor response, strategies to stimulate T cell response create new opportunities in DC cell biology, where DC maturation and antigen presentation are paramount. DC1 subtype is known for antigen-cross presentation to CD8 +T cells and the DC2 subtype to CD4 +T-cells. Previous studies showed that the immune chaperone GP96 plays a pivotal role in the processes of innate receptors. As a subject of interest from our lab, the GP96 client network offers potential targets to be explored for improving DC functions. We reported an increase in DC2 infiltration on the tumor side and a reduction of tumor growth in DC-specific GP96 deficient mice. Notwithstanding, the mechanism of GP96 in regulating DC functions is the subject of our study. By using in vitro approach, our study shows improvement in DC differentiation through gene expression assay, where DC subtypes display differential dependence on ER chaperone proteins. Also, the deletion of GP96 in DCs improves immunostimulatory activation and inhibits regulatory functions. Lastly, GP96 deficient DCs increased OVA antigen uptake and showed less T-cell exhaustion profile from in vivo tumor model. Directly DC activation or bypassing regulatory pathways can unleash T-cell response. Our study provides new insights into the role of GP96 in DCs in directing adaptive immune responses in the tumor microenvironment. This work was supported by the Pelotonia Institute of Immuno-Oncology (PIIO). The work was also supported in part by NIH/NCI (CA193939) and NIH/NIAID (AI125859) and supported by the Flow Cytometry Shared Resource at The Ohio State University Comprehensive Cancer Center and NIH/NCI P30 (CA138313).