Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy

Authors

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

Publication Date

11-26-2024

Journal

Cell Reports

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

Animals, Cancer Vaccines, Receptors, Immunologic, Macrophages, Mice, Immune Checkpoint Inhibitors, CD8-Positive T-Lymphocytes, Antigens, Neoplasm, Mice, Inbred C57BL, Membrane Glycoproteins, Female, Humans, CTLA-4 Antigen, Immunotherapy, Programmed Cell Death 1 Receptor, Mannose Receptor, Cell Line, Tumor, 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.

DOI

10.1016/j.celrep.2024.114875

PMID

39446585

PMCID

PMC11785356

PubMedCentral® Posted Date

1-31-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes