Background As the most potent antigen presenting cells, dendritic cells (DCs) play essential roles in mounting efficient immune response against tumor cells. They take up tumor antigens in the tissues, process and present tumor antigens to T cells, thereby inducing tumor-specific T cell response. On the other hand, tumor cells create an immunosuppressive microenvironment to limit DC function as an immune escape mechanism. However, cellular factors regulating DC function and molecular mechanism by which tumor cells induce DC dysfunction are not fully understood. To search for such DC modulators, we identified a transcriptional co-activator, Quaking (QKI) to be downregulated in tumor microenvironment and may play a regulatory role in DC-induced anti-tumor immunity.

Methods To obtain DC-specific deletion of QKI or its partner PPARδ, CD11c-cre mice were bred with mice carrying qkfl/fl or ppardfl/fl. The phagocytic function of QKI- or PPARδ-deficient DCs, as well as their T cell activation capacities were evaluated in vitro. Subcutaneous tumor models, MC38 and B16F10, were implanted in QKI- or PPARδ-knockout mice and monitored for tumor growth. Immune checkpoint inhibitors (ICI), anti-PD1 and anti-CTLA4 antibodies were administrated to tumor-bearing mice to evaluate the contribution of DC-specific QKI/PPARδ to responsiveness of ICIs.

Results Consistent with our previous studies in neural stem cells and microglia, we found QKI and PPARδ enhance phagocytosis in DCs by upregulating genes involved in the formation of phagosome and endosomes. QKI- or PPARδ-deficient DCs showed reduced CD8+ T cell priming capacity in vitro. In vivo tumor models suggest DC-specific knocking out of QKI or PPARδ promoted the tumor growth. Furthermore, ablation of QKI or PPARδ in DCs limited the response to immune checkpoint blockade.

Conclusions We revealed a transcriptional regulation of antigen processing and presentation by DCs through QKI and PPARδ. Our data also suggest that perturbing this important function of DCs would subvert their anti-tumor activity, highlighting the pivotal role of DCs in an effective anti-tumor immune response.