Self-antigen disrupts cDC1 mediated antitumor responses.

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• Conventional dendritic cells (DCs) maintain tissue homeostasis by sampling antigens.
• DCs face challenges in reconciling conflicting signals from self and foreign antigens in the tumor microenvironment.
• Understanding how DCs handle co-incident antigens is crucial for cancer immunology.

Purpose of the Study:

• To investigate how individual dendritic cells process and present co-incident self, tumor, and microbial antigens.
• To determine the impact of multi-antigen processing on T cell priming in the context of cancer.

Main Methods:

• Utilized in vivo fluorescent reporter systems for simultaneous antigen tracking.
• Employed high-resolution imaging and endosomal profiling in murine models.
• Analyzed antigen uptake, intracellular processing, and cross-presentation in skin, tumors, and lymph nodes.

Main Results:

• Dendritic cells frequently acquire antigens from multiple sources, with localization influenced by antigen origin.
• Type 1 conventional DCs co-processing self and tumor antigens were prevalent in tumors and draining lymph nodes.
• Dual-antigen loaded DCs showed reduced capacity to prime tumor-specific CD8+ T cells and decreased tumor peptide presentation on MHCI.
• Cross-priming of self-antigen specific T cells was significantly increased in dual-antigen loaded DCs.

Conclusions:

• Multi-antigen processing by DCs can bias peptide loading away from tumor epitopes, limiting anti-tumor T cell responses.
• Modulating the tumor microenvironment's antigenic context or endosomal routing may restore DC-mediated anti-tumor immunity.