Ramirez-Valdez et al. showed in prophylactic and therapeutic MC38 tumor models that priming mice with a self-assembling peptide:TLR7/8 agonist nanoparticle and boosting i.v. with a replication-deficient chimp adenovirus (ChAdOx1) provoked greater specific CD8+ T cell responses that mediated tumor protection better than ChAdOx1 vaccination alone. A boost of ChAdOx1 “empty” vector also stimulated an innate immune response via STING-dependent IFN-I, which reduced Chil3 immunosuppressive monocyte and increased pro-inflammatory C1qb macrophage frequency in the TME, and activated cDC1s and CD8+ T cell responses to mediate tumor regression.
Contributed by Paula Hochman
ABSTRACT: Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 T cells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 T cell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 T cells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans.
Author Info: (1) Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA; Ludwig Institute for Cancer Research, Nuffield
Author Info: (1) Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (2) Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA. (3) Singapore Immunology Network, A(_)STAR, Singapore, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (4) Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA. (5) Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA. (6) Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA. (7) Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA. (8) Vaccitech North America, Baltimore, MD, USA. (9) Singapore Immunology Network, A(_)STAR, Singapore, Singapore; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore. (10) Singapore Immunology Network, A(_)STAR, Singapore, Singapore; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore; Institut National de la Sante et de la Recherche Medicale (INSERM), 94800 Villejuif, France. (11) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (12) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (13) Vaccitech North America, Baltimore, MD, USA. (14) Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA. Electronic address: rseder@mail.nih.gov.
