1. Peptide: MHC-based DNA vaccination strategy to activate natural killer cells by targeting killer cell immunoglobulin-like receptors
- Author
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Rebecca Fulton, Matthew D. Blunt, Leidy Y Bastidas-Legarda, Aymen Al-Shamkhani, Salim I. Khakoo, Laura España-Serrano, Pauline Rettman, Christelle Retière, Marta E Polak, Andres F. Vallejo, University of Southampton, Etablissement Français du Sang [Pays de la Loire] (EFS Pays de la Loire), EFS, Bernardo, Elizabeth, Etablissement Français du Sang [Nantes], and RETIERE, Christelle
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Cytotoxicity, Immunologic ,Cancer Research ,Adoptive cell transfer ,Skin Neoplasms ,medicine.medical_treatment ,Cell ,Melanoma, Experimental ,immunogenicity ,Lymphocyte Activation ,killer cells ,0302 clinical medicine ,Cancer immunotherapy ,Receptors, KIR ,vaccine ,Vaccines, DNA ,Immunology and Allergy ,Receptors, Immunologic ,RC254-282 ,0303 health sciences ,biology ,Liver Neoplasms ,Vaccination ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Killer Cells, Natural ,medicine.anatomical_structure ,Oncology ,Molecular Medicine ,Antibody ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Human leukocyte antigen ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,HLA-C Antigens ,Major histocompatibility complex ,Cancer Vaccines ,DNA vaccination ,03 medical and health sciences ,Immune system ,Lymphocytes, Tumor-Infiltrating ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,medicine ,innate ,Animals ,Humans ,Lectins, C-Type ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,030304 developmental biology ,natural ,Pharmacology ,Immune Cell Therapies and Immune Cell Engineering ,immunity ,Mice, Inbred C57BL ,Haplotypes ,biology.protein ,Cancer research ,Peptides ,030215 immunology - Abstract
BackgroundNatural killer (NK) cells are increasingly being recognized as agents for cancer immunotherapy. The killer cell immunoglobulin-like receptors (KIRs) are expressed by NK cells and are immunogenetic determinants of the outcome of cancer. In particular, KIR2DS2 is associated with protective responses to several cancers and also direct recognition of cancer targets in vitro. Due to the high homology between activating and inhibitory KIR genes to date, it has been challenging to target individual KIR for therapeutic benefit.MethodsA novel KIR2DS2-targeting therapeutic peptide:MHC DNA vaccine was designed and used to immunize mice transgenic for KIR genes (KIR-Tg). NK cells were isolated from the livers and spleens of vaccinated mice and then analyzed for activation by flow cytometry, RNA profiling and cytotoxicity assays. In vivo assays of NK cell function using a syngeneic cancer model (B16 melanoma) and an adoptive transfer model for human hepatocellular carcinoma (Huh7) were performed.ResultsInjecting KIR-Tg mice with the vaccine construct activated NK cells in both liver and spleens of mice, with preferential activation of KIR2DS2-positive NK cells. KIR-specific activation was most marked on the CD11b+CD27+ mature subset of NK cells. RNA profiling indicated that the DNA vaccine upregulated genes associated with cellular metabolism and downregulated genes related to histone H3 methylation, which are associated with immune cell maturation and NK cell function. Vaccination led to canonical and cross-reactive peptide:MHC-specific NK cell responses. In vivo, DNA vaccination led to enhanced antitumor responses against B16F10 melanoma cells and also enhanced responses against a tumor model expressing the KIR2DS2 ligand HLA-C*0102.ConclusionWe show the feasibility of a peptide-based KIR-targeting vaccine strategy to activate NK cells and hence generate functional antitumor responses. This approach does not require detailed knowledge of the tumor peptidomes nor HLA matching with the patient. It therefore offers a novel opportunity for targeting NK cells for cancer immunotherapy.
- Published
- 2021
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