Cross-Presenting XCR1+ Dendritic Cells as Targets for Cancer Immunotherapy

Abstract

The use of dendritic cells (DCs) to generate effective anti-tumor T cell immunity has garnered much attention over the last thirty-plus years. Despite this, limited clinical benefit has been demonstrated thus far. There has been a revival of interest in DC-based treatment strategies following the remarkable patient responses observed with novel checkpoint blockade therapies, due to the potential for synergistic treatment. Cross-presenting DCs are recognized for their ability to prime CD8⁺ T cell responses to directly induce tumor death. Consequently, they are an attractive target for next-generation DC-based strategies. In this review, we define the universal classification system for cross-presenting DCs, and the vital role of this subset in mediating anti-tumor immunity. Furthermore, we will detail methods of targeting these DCs both ex vivo and in vivo to boost their function and drive effective anti-tumor responses.

Keywords: DC-based therapy; cancer; cross-presenting dendritic cells; immunotherapy.

Figure 1

Critical considerations for DC vaccination. DCs may be isolated from patients or generated in vitro. New protocols designed to specifically generate large amounts of XCR1⁺ DCs, rather than MoDCs, may prove beneficial. Ex vivo culture with cytokines and/or TLR/STING agonists upregulates maturation markers on antigen-loaded DCs, and increases cytokine and chemokine secretion. Activated XCR1⁺ DCs are typically injected intradermally, although intranodal improves efficiency of DCs reaching the LNs. Upregulation of CCR7 expression aids in DC migration to the LNs, where they cross-present pre-loaded antigen to naïve CD8⁺ T cells.

Figure 2

Schematic of in vivo XCR1⁺ DC activation to induce tumor cell death. Administration of cytokines, TLR/STING agonists, co-stimulatory molecules, and targeting antibody–antigen complexes can activate migratory (CD103⁺) XCR1⁺ DC in the tumor and lymphoid-resident XCR1⁺ DC. This can promote antigen acquisition, DC maturation, cross-presentation, and recruitment to the tumor site, culminating in increased CD8⁺ T cell-mediated tumor death.