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

• Published in: Cell reports (Cambridge) Vol. 43; no. 11; p. 114875
• Main Authors: Keshari, Sunita, Shavkunov, Alexander S., Miao, Qi, Saha, Akata, Minowa, Tomoyuki, Molgora, Martina, Williams, Charmelle D., Chaib, Mehdi, Highsmith, Anna M., Pineda, Josué E., Alekseev, Sayan, Alspach, Elise, Hu, Kenneth H., Colonna, Marco, Pauken, Kristen E., Chen, Ken, Gubin, Matthew M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26-11-2024; Elsevier
• Subjects: anti-CTLA-4/anti-PD-1; cancer immunotherapy; CD4 T cells; combination immunotherapy; CP: Cancer; CP: Immunology; immune checkpoint therapy; intratumoral macrophages; neoantigen cancer vaccines; neoantigen-specific CD8 T cells; TREM2; tumor microenvironment; CP: Immunology; neoantigen-specific CD8 T cells; immune checkpoint therapy; CP: Cancer; cancer immunotherapy; intratumoral macrophages; combination immunotherapy; neoantigen cancer vaccines; anti-CTLA-4/anti-PD-1; CD4 T cells; TREM2; tumor microenvironment
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114875

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-1+TCF-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 ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines maintain CX3CR1+CD206+ macrophages expressing the TREM2 receptor, unlike ICT, which suppresses them. TREM2 blockade enhances neoAg vaccine efficacy and is associated with fewer CX3CR1+CD206+ 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.
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•NeoAg vaccines utilize mechanisms partially distinct from those of αCTLA-4 or αPD-1•NeoAg vaccines potently induce TCF-1+ stem-like and proliferating neoAg-specific CD8 T cells•NeoAg vaccines induce macrophage remodeling partially distinct from that of αCTLA-4 or αPD-1•TREM2 blockade remodels intratumoral macrophages and enhances neoAg vaccine efficacy
Keshari et al. demonstrate in preclinical models that neoantigen peptide-based vaccines, anti-PD-1, and anti-CTLA-4 each induce partially distinct tumor microenvironment remodeling. Targeting intratumoral macrophages via TREM2 blockade extends the therapeutic window of neoantigen vaccines and is associated with a decrease in CX3CR1+CD206+ macrophages and the promotion of neoantigen-specific T cells.