CAFs/tumor Cells Co-Targeting DNA Vaccine in Combination with Low-Dose Gemcitabine for the Treatment of Panc02 Murine Pancreatic Cancer
Molecular therapy oncolytics(2022)
摘要
In this study, we investigate the synergistic effect of gemcitabine (Gem) and a novel DNA vaccine in the treatment of pancreatic cancer in mice and explore the anti-tumor mechanism of this combination therapy. Fibroblast activation protein α-expressing cancer-associated fibroblasts (FAPα+ CAFs), a dominant component of the tumor microenvironment (TME), have been shown to modulate the extracellular matrix (ECM) to promote the growth, invasion, and metastasis of pancreatic cancer (PC). Therefore, FAPα+ CAFs may be an ideal target for the treatment of PC. However, treatments that solely target FAPα+ CAFs do not directly affect tumor cells. We recently constructed a novel chimeric DNA vaccine (OsFS) against human FAPα and survivin, which simultaneously targets FAPα+ CAFs and tumor cells. In Panc02 tumor-bearing mice, OsFS vaccination not only reduced the proportion of immunosuppressive cells but also promoted the recruitment of tumor-infiltrating lymphocytes, which remodeled the TME to support anti-tumor immune responses. Furthermore, after depletion of regulatory T cells (Tregs) by metronomic low-dose Gem therapy, the anti-tumor effects of OsFS were enhanced. Taken together, our results indicate that the combination of the FAPα/survivin co-targeting DNA vaccine and low-dose Gem may be an effective therapy for PC.
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关键词
fibroblast activating protein α,gemcitabine,pancreatic cancer,tumor microenvironment,regulatory T cells,survivin,vaccine
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