Garrido et. al. describe a broadly applicable non-mutated neoantigen vaccine strategy of using TAP siRNA conjugated to a CpG oligonucleotide to downregulate TAP mRNA in dendritic cells, resulting in presentation of novel T cell epitopes due to impaired peptide processing. CpG-TAP siRNA vaccination alone protected against challenge with TAP-deficient tumor cells and silencing TAP with tumor-targeted TAP siRNA in tumors combined with vaccinating with CpG-TAP siRNA mediated s.c. and orthotopic tumor control without detectable toxicities, which could be a strategy readily applicable to a wide range of patients, even with intrinsically low neoantigen load.
Contributed by Alex Najibi
ABSTRACT: Vaccination of patients against neoantigens expressed in concurrent, recurrent, or tumors developing in individuals at risk of cancer is posing major challenges in terms of which antigens to target and is limited to patients expressing neoantigens in their tumors. Here, we describe a vaccination strategy against antigens that were induced in tumor cells by downregulation of the peptide transporter associated with antigen processing (TAP). Vaccination against TAP downregulation-induced antigens was more effective than vaccination against mutation-derived neoantigens, was devoid of measurable toxicity, and inhibited the growth of concurrent and future tumors in models of recurrence and premalignant disease. Human CD8+ T cells stimulated with TAPlow dendritic cells elicited a polyclonal T-cell response that recognized tumor cells with experimentally reduced TAP expression. Vaccination against TAP downregulation-induced antigens overcame the main limitations of vaccinating against mostly unique tumor-resident neoantigens and could represent a simpler vaccination strategy that will be applicable to most patients with cancer.
Author Info: (1) Microbiology & Immunology, University of Miami Miller School of Medicine. (2) M&I, University of Miami Miller School of Medicine. (3) Sylvester Comprehensive Cancer Center, Uni
Author Info: (1) Microbiology & Immunology, University of Miami Miller School of Medicine. (2) M&I, University of Miami Miller School of Medicine. (3) Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine. (4) Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine. (5) Department of Surgery, University of Miami Miller School of Medicine. (6) Obstetrics and Gynecology, University of Southern California. (7) University of Miami Miller School of Medicine. (8) Medical Oncology, Leiden University Medical Center. (9) Immuno-Oncology, Beckman Res. Inst. City of Hope. (10) Department of Public Health, University of Miami, Miller School of Medicine, Sylvester Comprehensive Cancer Center. (11) Immuno-Oncology, Beckman Res. Inst. City of Hope. (12) Departments of Molecular Microbiology & Immunology and Obstetrics & Gynecology, Norris Comprehensive Cancer Center, , University of Southern California. (13) Surgery, University of Miami. (14) Medical Oncology, Leiden University Medical Center. (15) University of Miami Miller School of Medicine egilboa@umail.miami.edu.
