BioProject

Cross-presentation of tumor antigens by dendritic cells (DCs) is crucial to prime and (re-) stimulate CD8+ T cells. More...

Cross-presentation of tumor antigens by dendritic cells (DCs) is crucial to prime and (re-) stimulate CD8+ T cells. This process is important in initiating and maintaining an anti-tumor response. Here, we show that tumor presence of conventional type 1 DCs (cDC1), a subtype that excels in cross-presentation, correlates with response to neoadjuvant immune checkpoint blockade (ICB) in melanoma. This led us to hypothesize that patients failing to respond to ICB could benefit from enhanced cross-presentation of tumor antigens. We therefore established a cross-presentation assay to screen over 5,500 compounds for enhancers of DC cross-presentation using induced T cell proliferation as readout. We identified 145 enhancers, including AZD5582, an antagonist of inhibitor of apoptosis proteins (IAPs) cIAP1, cIAP2 and XIAP. AZD5582 treatment led to DC activation of the non-canonical nuclear factor kappa B (NF-kB) pathway, enhanced antigen import from endolysosomes into the cytosol and increased expression of genes involved in cross-presentation. Furthermore, it upregulated expression of CD80, CD86, MHC class II, CD70 and secretion of TNF by DCs. This enhanced DC activation and maturation program was observed also in tumor-bearing mice upon AZD5582 treatment, culminating into an increased frequency of systemic tumor antigen-specific CD8+ T cells. Our results merit further exploration of AZD5582 to increase antigen cross-presentation for improving the clinical benefit of ICB in unfavorable patients. Overall design: GM-CSF DCs ('moDCs') (n=3 biological replicates) and FLT3L + GM-CSF DCs ('cDC1') (n=3 biological replicates) were treated with different contrations of AZD5582 for 24 hours (0.05-1 uM). A time point 0 and DMSO treated control are included. Less...