Using a murine mammary tumor model and a Clec9A-diphtheria toxin receptor mouse that can be depleted of specialized cross-presenting CD8α+ and CD103+ (DC1) subsets, Gilfillan et al. determined that in the context of poly I:C immunotherapy, DC1 subsets were not essential to mount a CD8+ T cell mediated antitumor response; both DC1 and XCR1- DC2 subsets were able to take up tumor antigens in vivo, and could cross-present antigen to T cells in vitro. While the DC1 cells were more effective as stimulators, DC2s were more abundant in draining lymph nodes.

In the steady state, tumors harbor several populations of dendritic cells (DCs) and myeloid cells that are key regulators of the intratumoral immune environment. Among these cells, migratory CD103(+) cross-presenting DCs are thought to be critical for tumor-specific CTL responses and tumor resistance. However, it is unclear whether this prominent role also extends to immunotherapy. We used a murine orthotopic mammary tumor model, as well as Clec9A-diphtheria toxin receptor mice that can be depleted of the specialized cross-presenting CD8alpha(+) and CD103(+) DC1 subsets, to investigate the role of these DCs in immunotherapy. Treatment with monosodium urate crystals and mycobacteria at the tumor site delayed tumor growth and required DC1s for efficacy. In contrast, treatment with poly I:C was equally effective regardless of DC1 depletion. Neither treatment affected myeloid-derived suppressor cell numbers in the spleen or tumor. Similar experiments using subcutaneous B16 melanoma tumors in BATF3-knockout mice confirmed that CD103(+) DCs were not necessary for successful poly I:C immunotherapy. Nevertheless, adaptive immune responses were essential for the response to poly I:C, because mice depleted of CD8(+) T cells or all DC subsets were unable to delay tumor growth. In vivo experiments showed that DC1 and DC2 subsets were able to take up tumor Ags, with DC2s making up the larger proportion of lymph node DCs carrying tumor material. Both DC subsets were able to cross-present OVA to OT-I T cells in vitro. Thus, immunotherapy with poly I:C enables multiple DC subsets to cross-present tumor Ag for effective antitumor immune responses.

Author Info: (1) Malaghan Institute of Medical Research, Wellington 6021, New Zealand. University of Otago, Wellington, Wellington 6021, New Zealand; and. (2) Malaghan Institute of Medical Research

Author Info: (1) Malaghan Institute of Medical Research, Wellington 6021, New Zealand. University of Otago, Wellington, Wellington 6021, New Zealand; and. (2) Malaghan Institute of Medical Research, Wellington 6021, New Zealand. (3) Malaghan Institute of Medical Research, Wellington 6021, New Zealand. (4) Malaghan Institute of Medical Research, Wellington 6021, New Zealand. (5) Malaghan Institute of Medical Research, Wellington 6021, New Zealand. (6) School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore. (7) Malaghan Institute of Medical Research, Wellington 6021, New Zealand; fronchese@malaghan.org.nz.

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