Critical Role for CD103+/CD141+ Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma

• Published in: Cancer cell 2016-08, Vol.30 (2), p.324-336
• Main Authors: Roberts, Edward W., Broz, Miranda L., Binnewies, Mikhail, Headley, Mark B., Nelson, Amanda E., Wolf, Denise M., Kaisho, Tsuneyasu, Bogunovic, Dusan, Bhardwaj, Nina, Krummel, Matthew F.
• Format: Article
• Language: English
• Subjects: 2-photon imaging; Animals; anti-tumor T cell priming; Antigen Presentation; antigen trafficking; Antigens, CD - immunology; Antigens, Neoplasm - immunology; Antigens, Surface - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Movement - immunology; dendritic cells; Dendritic Cells - immunology; Dendritic Cells - pathology; draining lymph node; Humans; Integrin alpha Chains - immunology; Lymph Nodes - immunology; Lymph Nodes - pathology; melanoma; Melanoma - immunology; Melanoma - pathology; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, CCR7 - immunology; Thrombomodulin; tumor; tumor immune response
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2016.06.003

Intratumoral dendritic cells (DC) bearing CD103 in mice or CD141 in humans drive intratumoral CD8+ T cell activation. Using multiple strategies, we identified a critical role for these DC in trafficking tumor antigen to lymph nodes (LN), resulting in both direct CD8+ T cell stimulation and antigen hand-off to resident myeloid cells. These effects all required CCR7. Live imaging demonstrated direct presentation to T cells in LN, and CCR7 loss specifically in these cells resulted in defective LN T cell priming and increased tumor outgrowth. CCR7 expression levels in human tumors correlate with signatures of CD141+ DC, intratumoral T cells, and better clinical outcomes. This work identifies an ongoing pathway to T cell priming, which should be harnessed for tumor therapies. [Display omitted] •Tumor antigen trafficking and “painting” identify LN trafficking immune cells•CD103+ DC are critical tumor-draining antigen-presenting cells driving CD8+ T cells•CCR7 on CD103+ DC is required for tumor antigen drainage and T cell activation•CCR7 level in human melanoma correlates with T cell infiltration and patient survival Roberts et al. show that intratumoral CD103+ dendritic cells (DC) in mice, or CD141+ DC in humans, traffic tumor antigens to lymph nodes to prime CD8+ T cells, which requires CCR7 on these DC. High CCR7 expression level in human tumors correlates with signatures of CD141+ DC and better clinical outcomes.