Vaccines have been hailed as one of the most remarkable medical advancements in human history, and their potential for treating
cancer by generating or expanding anti-
tumor T cells has garnered significant interest in recent years. However, the limited efficacy of therapeutic
cancer vaccines in clinical trials can be partially attributed to the inadequacy of current preclinical mouse models in recapitulating the complexities of the human immune system. In this study, we developed two innovative humanized mouse models to assess the immunogenicity and therapeutic effectiveness of
vaccines targeting human papillomavirus (HPV16)
antigens and delivering
tumor antigens to human CD141+ dendritic cells (DCs). Both models were based on the transference of human peripheral blood mononuclear cells (PBMCs) into immunocompromised
HLA-A*02-NSG mice (NSG-A2), where the use of fresh PBMCs boosted the engraftment of human cells up to 80%. The dynamics of immune cells in the PBMC-hu-NSG-A2 mice demonstrated that T cells constituted the vast majority of engrafted cells, which progressively expanded over time and retained their responsiveness to ex vivo stimulation. Using the PBMC-hu-NSG-A2 system, we generated a hyperplastic skin graft model expressing the HPV16-E7 oncogene. Remarkably, human cells populated the skin grafts, and upon vaccination with
a DNA vaccine encoding an HPV16-E6/E7
protein, rapid rejection targeted to the E7-expressing skin was detected, underscoring the capacity of the model to mount a
vaccine-specific response. To overcome the decline in DC numbers observed over time in PBMC-hu-NSG-A2 animals, we augmented the abundance of CD141+ DCs, the specific targets of our tailored nanoemulsions (TNEs), by transferring additional autologous PBMCs pre-treated in vitro with the
growth factor Flt3-L. The Flt3-L treatment bolstered CD141+ DC numbers, leading to potent
antigen-specific CD4+ and CD8+ T cell responses in vivo, which caused the regression of pre-established
triple-negative breast cancer and
melanoma tumors following CD141+ DC-targeting TNE vaccination. Notably, using
HLA-A*02-matching PBMCs for humanizing NSG-A2 mice resulted in a delayed onset of
graft-versus-host disease and enhanced the efficacy of the TNE vaccination compared with the parental NSG strain. In conclusion, we successfully established two humanized mouse models that exhibited strong
antigen-specific responses and demonstrated
tumor regression following vaccination. These models serve as valuable platforms for assessing the efficacy of therapeutic
cancer vaccines targeting HPV16-dysplastic skin and diverse
tumor antigens specifically delivered to CD141+ DCs.