Document text
Principal Investigator: Daniel Abate-Daga
Organization: H. LEE MOFFITT CANCER CTR & RES INST
Fiscal Year: 2024
Award: $224,506
Funding agency: National Cancer Institute
Project Summary
Killer cell immunoglobulin-like receptors (KIR) are mainly expressed by NK cells, although their
expression has also been described in CD4+, CD8+ and γδ T cells. Within CD8 T cells, KIR expression is
induced at later stages of lymphocyte maturation and is thought to regulate specific T cell effector functions.
Within KIR receptors, KIR2DL2 modulates T cell effector functions, as KIR2DL2+ CD8+ T cells present
reduced level of activation-induced cell death, and poor IFN-γ secretion after T cell receptor (TCR)
stimulation. The notion of a suppressive function of KIR2DL2 expression in CD8+ T cells is supported by the
observation that patients that express its cognate ligand, HLA-C1, showed decreased overall survival and
could not control tumor growth. Our preliminary data show that KIR2DL2 expression increases in vivo in
adoptively transferred T cells in patients and in preclinical models of adoptive immunotherapy. Using a
pancreatic tumor model, we found that chimeric antigen receptor (CAR)-T cells expressing KIR2DL2 were
significantly less cytotoxic than their KIR2DL2- counterparts in presence of KIR2DL2’s ligand. Furthermore,
KIR2DL2 expression in CAR-T cells was associated with reduced antitumor efficacy, in an HLA-I-dependent
manner, in a murine model of pancreatic cancer. Based on these preliminary findings we hypothesize that
KIR2DL2 behaves as a T cell immune checkpoint, modulating T cell effector function and leading to
an ineffective immunosurveillance. Therefore, targeting KIR2DL2 during T cell manufacturing may
improve T cell performance after cell infusion. We will test our hypothesis by 1) Defining the modulatory
mechanisms whereby KIR2DL2 shapes CAR- and TCR-transgenic T cell antitumoral effector function. We
will determine the overall effect of KIR2DL2 engagement in TCR-transgenic and CAR-T cell effector function.
Additionally, we will determine which regions within KIR2DL2 are responsible for its modulatory function.
Finally, we will characterize both the KIR2DL2 signaling interactome and the downstream events triggered
by its ligand interaction by immunoprecipitation and proteomic analyses. 2) Improving T cell performance for
the enhancement of adoptive cell immunotherapies (ACTs) by abrogating KIR2DL2 function. To prevent its
inhibitory effect, manipulation of KIR2DL2 expression and/or signaling will be conducted and adapted to the
current protocols for CAR-T cell manufacturing. Based on the anticipated results, we will link for the first time
the biological and molecular function of KIR2DL2 within therapeutic T cells. The proposed studies will
increase our mechanistic understanding of KIR2DL2 biology and will generate novel cell products with high
translational potential.
Terms: <Ablation><Adoptive Cellular Immunotherapy><Adoptive Immunotherapy><Animal Model><Animal Models and Related Studies><Assay><Autoimmune Status><Autoimmunity><Binding><Bioassay><Biological><Biological Assay><Biology><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CRISPR><CRISPR/Cas system><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Death Induction><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular biology><Clinical><Clonal Expansion><Clustered Regularly Interspaced Short Palindromic Repeats><Conditioned Reflex><Cytotoxic cell><Data><Docking><Education><Educational aspects><Elements><Event><Gamma-delta T cells><Gene Transcription><General Population><General Public><Genes><Genetic><Genetic Transcription><Genomics><Goals><HCPH><HLA-C><HLA-C Antigens><Hematopoietic Cell Phosphatase><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><ITIM><Immune><Immune Globulins><Immune Interferon><Immune Precipitation><Immune Surveillance><Immune mediated therapy><Immunes><Immunoblotting><Immunoglobulins><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunologically Directed Therapy><Immunoprecipitation><Immunoreceptor Tyrosine-Based Inhibitory Motif><Immunosurveillance><Immunotherapy><Impairment><Infusion><Infusion procedures><Interferon Gamma><Interferon Type II><Intracellular Communication and Signaling><K Cells><K lymphocyte><Killer Cells><Knowledge acquisition><LYT3><Ligands><Link><Liquid substance><Lymphatic cell><Lymphocyte><Lymphocytic><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Measures><Mediating><Melanoma patient><Memory><Methods><Modeling><Modern Man><Modification><Molecular><Molecular Interaction><Molecular Mechanisms of Action><NK Cells><Natural Killer Cells><Nonreceptor Type 6 Protein-Tyrosine Phosphatase><Outcome><PTP-1C><PTP1C><PTPN6><PTPN6 gene><Pancreas Cancer><Pancreatic Cancer><Pathway interactions><Patient observation><Patients><Performance><Pre-Clinical Model><Preclinical Models><Protein-Tyrosine Phosphatase 1C><Proteomics><Protocol><Protocols documentation><RNA Expression><Receptor Protein><Research><Role><SHP-1><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Solid Neoplasm><Solid Tumor><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><Teff cell><Testing><Time><Transcription><Transgenic Organisms><Tumor Cell><Tyrosine><Tyrosine phosphatase SHP1><Up-Regulation><Upregulation><Viral Diseases><Virus Diseases><Watchful Waiting><Western Blotting><Western Immunoblotting><Xenograft Model><activate T cells><adoptive T cell transfer><adoptive T-cell therapy><adoptive cell immunotherapy><biologic><biological signal transduction><cell biology><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><conditioned response><cytokine><cytotoxic><design><designing><effector T cell><engineered T cells><fluid><genetically engineered T-cells><genome editing><genomic editing><immune cell check points><immune cell checkpoints><immune check point><immune checkpoint><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><improved><in vivo><infusions><killer immunoglobulin-like receptor><lFN-Gamma><liquid><lymph cell><malignancy><manufacture><model of animal><mouse model><murine model><mutant><neoplasm/cancer><neoplastic cell><novel><overexpress><overexpression><pancreatic cancer model><pancreatic malignancy><pancreatic tumor model><pathway><pharmacologic><prevent><preventing><protein blotting><receptor><receptor binding><receptor bound><receptor expression><social role><therapeutic T-cell platform><thymus derived lymphocyte><transgenic><transgenic T- cells><translational opportunities><translational potential><tumor><tumor growth><viral infection><virus infection><virus-induced disease><xenograft transplant model><xenotransplant model><γδ T cells><γδT cells>