Abstract
Dendritic cell (DC) vaccines targeting only cancer cells have produced limited antitumor activity in most clinical studies. Targeting cancer-associated fibroblasts (CAFs) in addition to cancer cells may enhance antitumor effects, since CAFs, the central component of the tumor stroma, directly support tumor growth and contribute to the immunosuppressive tumor microenvironment. To co-target CAFs and tumor cells we developed a new compound DC vaccine that encodes an A20-specific shRNA to enhance DC function, and targets fibroblast activation protein (FAP) expressed in CAFs and the tumor antigen tyrosine-related protein (TRP)2 (DC-shA20-FAP-TRP2). DC-shA20-FAP-TRP2 vaccination induced robust FAP- and TRP2-specific T-cell responses, resulting in greater antitumor activity in the B16 melanoma model in comparison to monovalent vaccines or a vaccine encoding antigens and a control shRNA. DC-shA20-FAP-TRP2 vaccination enhanced tumor infiltration of CD8-positive T cells, and induced antigen-spreading resulting in potent antitumor activity. Thus, co-targeting of tumor cells and CAFs results in the induction of broad-based tumor-specific T-cell responses and has the potential to improve current vaccine approaches for cancer.
Highlights
Dendritic cell (DC) vaccines have shown limited antitumor activity in the majority of clinical trials [1]
To demonstrate that Lv-transduced DCs induce fibroblasts activating protein (FAP)- and TRP2-specific T-cell responses, mice were vaccinated with 16106 DC-shA20-FAP, DC-shA20-TRP2, DC-shA20-FAP-TRP2, or DC-shCo-FAP-TRP2
TRP2-specific T cells was determined by IFN-c Enzyme-linked immunosorbent spot (Elispot) assays
Summary
Dendritic cell (DC) vaccines have shown limited antitumor activity in the majority of clinical trials [1]. This lack of efficacy is most likely due to the presence of immunosuppressive cells within the tumor as well as the tumor supporting stroma limiting cross presentation and the induction of broad-based tumor antigenspecific T-cell responses [2,3]. CAFs express fibroblasts activating protein (FAP) [11] and the targeted deletion of FAP-positive CAFs in transgenic mouse models has potent antitumor effects highlighting their central role in tumorigenesis [12]. FAP-targeted vaccines reduced tumor collagen content and modulated the tumor immune microenvironment in preclinical models [13,14]
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