Inhibitor of Apoptosis Proteins Antagonist Induces T-cell Proliferation after Cross-Presentation by Dendritic Cells

Cross-presentation of tumor antigens by dendritic cells (DC) is crucial to prime, stimulate and restimulate CD8+ T cells. This process is important in initiating and maintaining an antitumor response. Here, we show that the presence of conventional type 1 DCs (cDC1), a DC subtype that excels in cross-presentation, in the tumor correlated 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 the readout. We identified 145 enhancers, including AZD5582, an antagonist of inhibitor of apoptosis proteins (IAP) cIAP1, cIAP2, and XIAP. AZD5582 treatment led to DC activation of the noncanonical 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 in 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 patients who are unlikely to respond to ICB.

 

Comments：

The ability of dendritic cells (DCs) to cross-present tumor antigens to CD8+ T cells is essential for inducing and maintaining an antitumor response. However, some patients do not respond to neoadjuvant immune checkpoint blockade (ICB), which can be due to inefficient cross-presentation of tumor antigens by DCs. In this study, the presence of conventional type 1 DCs (cDC1), a DC subtype that excels in cross-presentation, in the tumor correlated with response to ICB in melanoma.

To enhance DC cross-presentation, the researchers established a screening assay to identify compounds that could enhance cross-presentation. The assay involved induced T-cell proliferation as the readout, and they screened over 5,500 compounds. They identified 145 enhancers, including AZD5582, which is an antagonist of inhibitor of apoptosis proteins (IAP) cIAP1, cIAP2, and XIAP.

The researchers found that AZD5582 treatment led to DC activation of the noncanonical NF-kB pathway, which enhanced antigen import from endolysosomes into the cytosol and increased the expression of genes involved in cross-presentation. Furthermore, AZD5582 upregulated the expression of CD80, CD86, MHC class II, CD70, and secretion of TNF by DCs. These changes led to an enhanced DC activation and maturation program, which was also observed in tumor-bearing mice upon AZD5582 treatment. Finally, AZD5582 treatment resulted in an increased frequency of systemic tumor antigen-specific CD8+ T cells.

These results suggest that AZD5582 could be used to increase antigen cross-presentation to improve the clinical benefit of ICB in patients who are unlikely to respond to ICB. Further studies are needed to explore the potential of AZD5582 in the clinic.