Temporally Programmed CD8α+ DC Activation Enhances Combination Cancer Immunotherapy

Numerous synergistic cancer immunotherapy combinations have been identified, but the effects of relative dose timing are rarely considered. In established syngeneic mouse tumor models, we found that staggering interferon-α (IFNα) administration after, rather than before or simultaneously with, serum-persistent interleukin-2 (IL-2) and tumor-specific antibody significantly increased long-term survival. Successful combination therapy required IFNα-induced activation of cross-presenting CD8α+ dendritic cells (DCs) following the release of antigenic tumor debris by the IL-2- and antibody-mediated immune response. Due to decreased phagocytic ability post-maturation, DCs activated too early captured less antigen and could not effectively prime CD8+ T cells. Temporally programming DC activation to occur after tumoricidal activity enhanced tumor control by multiple distinct combination immunotherapies, highlighting dose schedule as an underappreciated factor that can profoundly affect the success of multi-component immunotherapies. [Display omitted] •Relative timing of IFNα dose in combination cancer immunotherapy alters outcomes•CD8α+ DCs exposed to IFNα undergo maturation and lose phagocytic ability•Only DCs matured after antigenic tumor debris generation prime long-term immunity•Other DC activators also show schedule-dependent synergy with cytotoxic therapies Dose timing is an often overlooked variable that can influence combination immunotherapy outcomes. Tzeng et al. show that, while premature activation of antigen-presenting cells diminishes their ability to trigger immune responses to subsequently available tumor antigen, programmed activation following tumoricidal activity exemplifies a broad approach for generating potent antitumor immunity.