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

Cancer-associated fibroblasts (CAFs), which are dominant cell types in the tumor microenvironment (TME), support tumor growth by secreting cytokines and forming an extracellular matrix (ECM) that hampers the penetration of chemical and biological therapeutics within the tumor and thereby limits their therapeutic efficacy. Here, we report a cancer nanovaccine targeting fibroblast activation protein α (FAP)-expressing CAFs as a potential pan-tumor vaccine. We predicted immunodominant FAP-specific epitope peptides in silico and selected two candidate peptides after in vitro and in vivo screening for immunogenicity and antitumor efficacy. Next, we developed a nanoparticle-based vaccine that displays the two selected epitope peptides on the surface of lipid nanoparticles encapsulating CpG adjuvant (FAP_PEP-SLNPs). Immunization with one of two FAP_PEP-SLNP nanovaccines led to considerable growth inhibition of various tumors, including desmoplastic tumors, by depleting FAP⁺ CAFs and thereby reducing ECM production in the TME while causing little appreciable adverse effects. Furthermore, when combined with a chemotherapeutic drug, the FAP_PEP-SLNP nanovaccine increased drug accumulation and resulted in a synergistic antitumor efficacy far better than that of each corresponding monotherapy. These findings suggest that our FAP_PEP-SLNP nanovaccine has potential for use as an "off-the-shelf" pan-tumor vaccine applicable to a variety of tumors and may be a suitable platform for use in various combination therapies.