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

Sunita Keshari; Alexander S Shavkunov; Qi Miao; Akata Saha; Tomoyuki Minowa; Martina Molgora; Charmelle D Williams; Mehdi Chaib; Anna M Highsmith; Josué E Pineda; Sayan Alekseev; Elise Alspach; Kenneth H Hu; Marco Colonna; Kristen E Pauken; Ken Chen; Matthew M Gubin

doi:10.1016/j.celrep.2024.114875

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

Cell Rep. 2024 Oct 23;43(11):114875. doi: 10.1016/j.celrep.2024.114875. Online ahead of print.

Authors

Sunita Keshari¹, Alexander S Shavkunov¹, Qi Miao², Akata Saha¹, Tomoyuki Minowa¹, Martina Molgora³, Charmelle D Williams¹, Mehdi Chaib¹, Anna M Highsmith¹, Josué E Pineda¹, Sayan Alekseev⁴, Elise Alspach⁵, Kenneth H Hu⁶, Marco Colonna³, Kristen E Pauken¹, Ken Chen², Matthew M Gubin⁷

Affiliations

¹ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, St. Louis, MO, USA.
⁴ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Program of Biology, The University of Texas at San Antonio, San Antonio, TX, USA.
⁵ Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
⁶ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mgubin@mdanderson.org.

PMID: 39446585
DOI: 10.1016/j.celrep.2024.114875

Abstract

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.

Keywords: CD4 T cells; CP: Cancer; CP: Immunology; TREM2; anti-CTLA-4/anti-PD-1; cancer immunotherapy; combination immunotherapy; immune checkpoint therapy; intratumoral macrophages; neoantigen cancer vaccines; neoantigen-specific CD8 T cells; tumor microenvironment.