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
Affiliations
Sunita Keshari
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Alexander S. Shavkunov
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Qi Miao
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Akata Saha
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Tomoyuki Minowa
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Martina Molgora
Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, St. Louis, MO, USA
Charmelle D. Williams
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Mehdi Chaib
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Anna M. Highsmith
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Josué E. Pineda
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Sayan Alekseev
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
Elise Alspach
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA
Kenneth H. Hu
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
Marco Colonna
Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, St. Louis, MO, USA
Kristen E. Pauken
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ken Chen
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Matthew M. Gubin
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author
Summary: 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.
