Tumor-associated fibroblasts are key regulators of
tumorigenesis. In contrast to
tumor cells, which are genetically unstable and mutate frequently, the presence of genetically more stable fibroblasts in the
tumor-stromal compartment makes them an optimal target for
cancer immunotherapy. These cells are also the primary source of
collagen type I, which contributes to decreased chemotherapeutic drug uptake in
tumors and plays a significant role in regulating
tumor sensitivity to a variety of
chemotherapies. To specifically kill tumor-associated fibroblasts, we constructed an oral
DNA vaccine targeting fibroblast activation
protein (FAP), which is specifically overexpressed by fibroblasts in the
tumor stroma. Through CD8+ T cell-mediated killing of tumor-associated fibroblasts, our
vaccine successfully suppressed primary
tumor cell growth and
metastasis of multidrug-resistant murine colon and
breast carcinoma. Furthermore,
tumor tissue of FAP-vaccinated mice revealed markedly decreased
collagen type I expression and up to 70% greater uptake of chemotherapeutic drugs. Most importantly, pFap-vaccinated mice treated with
chemotherapy showed a 3-fold prolongation in lifespan and marked suppression of
tumor growth, with 50% of the animals completely rejecting a
tumor cell challenge. This strategy opens a new venue for the combination of immuno- and
chemotherapies.