Comparing neoantigen cancer vaccines and immune checkpoint therapy unveils an effective vaccine and anti-TREM2 macrophage-targeting dual therapy.

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1TCF-1 neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1 neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOSBhlhe40 T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS macrophages, neoAg vaccines maintain CX3CR1CD206 macrophages expressing the TREM2 receptor, unlike ICT, which suppresses them. TREM2 blockade enhances neoAg vaccine efficacy and is associated with fewer CX3CR1CD206 macrophages and induction of neoAg-specific CD8 T cells. Our findings highlight different mechanisms underlying neoAg vaccines and different forms of ICT and identify combinatorial therapies to enhance neoAg vaccine efficacy.