Abstract #360: A DNA vaccine against Fibroblast Activation Protein acts synergistically with doxorubicin to promote anti-tumor immunity in a mouse model of metastatic breast cancer.

Abstract

Tumor associated stroma differs from stroma in normal tissue in that it has an activated phenotype characterized by production of certain extracellular matrix components, growth factors, and cytokines. An activated stroma is associated with increased invasiveness of many epithelial cancers. Cancer associated fibroblasts (CAFs) constitute the major cell type in the tumor stroma and has an activated phenotype often characterized by expression of a transmembrane serine protease known as Fibroblast-activation Protein (FAP). FAP is overexpressed in 90% of CAFs associated with breast carcinomas. We utilized the FAP antigen as a novel target for a DNA vaccine and tested its efficacy in combination with doxorubicin in a mouse model of spontaneous metastatic breast cancer. Oral vaccination with the pFAP vaccine generated a CD8+ T cell dependent anti-tumor response. Additionally, vaccination resulted in a reduction of collagen type I expression in the primary tumors. When combined with chemotherapy, the decrease in collagen expression resulted in an increased uptake of doxorubicin into the primary tumor and increased tumor cell apoptosis resulting in enhanced suppression of tumor growth when compared to vaccination or chemotherapy alone. Using immunofluorescence staining, we show that mice treated with both the FAP-based DNA vaccine and doxorubicin have increased dendritic and CD8 positive cells and decreased macrophages and T regulatory cells in their primary tumors. Additionally, we find that CD8 positive lymphocytes isolated from mice treated with both the vaccine and doxorubicin exhibit enhanced proliferation and activation in response to stimulation with IL-2 or tumor antigen in vitro when compared to control or either treatment alone. These results suggest that targeting of activated fibroblasts within the tumor niche with a vaccine against pFAP in combination with chemotherapy can lead to attenuation of tumor-associated immune suppression resulting in increased anti-tumor immunity.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 360.