Nanovaccine Displaying Immunodominant T Cell Epitopes of Fibroblast Activation Protein Is Effective Against Desmoplastic Tumors

Cancer-associated fibroblasts (CAFs), which are dominantcell typesin the tumor microenvironment (TME), support tumor growth by secretingcytokines and forming an extracellular matrix (ECM) that hampers thepenetration of chemical and biological therapeutics within the tumorand thereby limits their therapeutic efficacy. Here, we report a cancernanovaccine targeting fibroblast activation protein alpha (FAP)-expressingCAFs as a potential pan-tumor vaccine. We predicted immunodominantFAP-specific epitope peptides in silico and selectedtwo candidate peptides after in vitro and in vivo screening for immunogenicity and antitumor efficacy.Next, we developed a nanoparticle-based vaccine that displays thetwo selected epitope peptides on the surface of lipid nanoparticlesencapsulating CpG adjuvant (FAP(PEP)-SLNPs). Immunizationwith one of two FAP(PEP)-SLNP nanovaccines led to considerablegrowth inhibition of various tumors, including desmoplastic tumors,by depleting FAP(+) CAFs and thereby reducing ECM productionin the TME while causing little appreciable adverse effects. Furthermore,when combined with a chemotherapeutic drug, the FAP(PEP)-SLNPnanovaccine increased drug accumulation and resulted in a synergisticantitumor efficacy far better than that of each corresponding monotherapy.These findings suggest that our FAP(PEP)-SLNP nanovaccinehas potential for use as an "off-the-shelf" pan-tumorvaccine applicable to a variety of tumors and may be a suitable platformfor use in various combination therapies.