Type I Interferon Regulation of Tumor Cell and Immune Cell Interaction in Human Colon Cancer
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Principal Investigator: KEBIN LIU Organization: CHARLIE NORWOOD VA MEDICAL CENTER Fiscal Year: 2024 Funding agency: Veterans Affairs Project Summary IFN was an FDA-approved agent for human cancer therapy and is currently used as exogenous recombinant protein or protein prodrugs. The use of IFN in human cancer therapy has been limited by the ineffective dosing and high toxicity. This proposal develops a lipid nanoparticle encapsulated IFN-encoding DNA nanoplasmid (IFNA13CO01) to force tumor cells to express and produce endogenous IFN13 locally in the tumor microenvironment. IFNA13CO01 therapy is therefore expected to produce high level of endogenous IFN13 locally in the tumor site and thus overcomes the ineffective dosing and systemic toxicity issues associated with the current IFN agents. In the preliminary studies, we determined that type I interferon (IFN-I: IFN and IFN) expression level is significantly lower in human colorectal carcinoma than in normal colon tissue. We further determined that IFN-I functions in both tumor cells and T cells are essential for host cancer immune surveillance. Mechanistically, we determined that IFN-I activates STAT3 that binds to the Gzmb promoter to activate Gzmb transcription in CTLs. The IFN-I/STAT3/Gzmb axis thus is essential for CTL anti- tumor function. In addition, we determined that tumor cell expressed PD-L1 (tPD-L1) engages myeloid cell expressed PD-1 (mPD-1) to antagonize IFN-I and STAT1 signaling to repress Cxcl9 and Cxcl10 to impair CTL recruitment to lung metastases. Human patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. We therefore discovered that the tPD-L1/mPD-1/IFN-I/STAT1/Cxcl9-Cxcl10 axis controls CTL tumor infiltration in lung metastasis. Our central hypothesis is that forcing tumor cells to express and produce endogenous IFN13 in the local tumor microenvironment via IFNA13CO01 therapy is an effective and yet safe approach to suppress human colorectal tumor growth and progression. We propose to test our new central hypothesis by pursuing the following 3 specific aims: 1) Test the hypothesis that tPD-1 engages mPD-1 to inhibit IFI-I signaling to suppress CTL recruitment and function to promote metastatic tumor growth in human colon cancer patients.; 2) Determine the efficacy of IFNA13CO01 in suppression of metastatic human colon cancer PDX growth in humanized NSG mice; and 3) Determine IFNA13CO01 biodistribution, toxicology and pharmacokinetics in vivo. Terms: <Alpha-Beta-Omega Interferon Receptor-1><Antigens><Antiviral Protein Alpha Type><B7-H1><B7H1><Binding><Biochemical><Biodistribution><Blast Transformation><Blastogenesis><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><CD274><Cancer Treatment><Cancers><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-Mediated Lympholytic Cells><Cell-to-Cell Interaction><Chimera><Chimera organism><Codon><Codon Nucleotides><Colon><Colon Cancer><Colon Carcinoma><Colon Neoplasms><Colon Tumor><Colonic Mass><Colonic Neoplasms><Colonic Tumor><Colorectal Cancer><Colorectal Carcinomas><Colorectal Neoplasms><Colorectal Tumors><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><DNA><Deoxyribonucleic Acid><Development><Dose><Drug Kinetics><Drug Precursors><Encapsulated><Exhibits><FDA approved><Funding><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><General Population><General Public><Generalized Growth><Genetic Transcription><Growth><Hepatic Neoplasm Secondary><Hepatic metastasis><HuIFN-Alpha-Rec><Human><IFNAR><IFNAR1><IFNAR1 gene><IFNBR><IFRC><Immune><Immune Surveillance><Immune mediated therapy><Immunes><Immunocompetent><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunologically Directed Therapy><Immunosurveillance><Immunotherapy><Impairment><Infiltration><Interferon Alpha-Beta Receptor Alpha Chain><Interferon Type I><Intracellular Communication and Signaling><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Large Bowel Carcinoma><Large Bowel Tumor><Large Intestine Carcinoma><Large Intestine Neoplasm><Large Intestine Tumor><Ligands><Liposomal><Liposomes><Liver secondaries><Liver secondary cancer><Lung><Lung Respiratory System><Lymphoblast Transformation><Lymphocyte Activation><Lymphocyte Stimulation><Lymphocyte Transformation><Lytic><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Metastasis><Metastasis to the Lung><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Liver><Metastatic Neoplasm to the Lung><Metastatic Tumor><Metastatic Tumor to the Liver><Metastatic Tumor to the Lung><Metastatic malignant neoplasm to liver><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Myeloid Cells><Neoplasm Metastasis><Non-Polyadenylated RNA><Null Mouse><PD 1><PD-1><PD-1 blockade><PD-1/PD-L1><PD-1/PDL1><PD-L1><PD1><PD1 blockade><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDL-1><PDL1><PDX model><Pathway interactions><Patient derived xenograft><Pharmacokinetics><Primary Neoplasm><Primary Tumor><Pro-Drugs><Prodrugs><Productivity><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteins><RNA><RNA Expression><RNA Gene Products><Recombinant Proteins><Regulation><Repression><Research Design><Resistance><Ribonucleic Acid><Role><STAT1><STAT1 gene><STAT3><STAT3 gene><STAT91><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Site><Study Type><Survival Rate><T-Cells><T-Lymphocyte><Testing><Tissue Growth><Tissues><Toxic effect><Toxicities><Toxicology><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Tumor Cell><Tumor Escape><Tumor Immune Escape><Tumor-Infiltrating Lymphocytes><Veterans><aPD-1><aPD1><aged><analyze gene expression><anti programmed cell death 1><anti-PD-1><anti-PD-1 blockade><anti-PD1><anti-PD1 blockade><anti-cancer immunotherapy><anti-cancer therapy><anti-programmed cell death protein 1><antiPD-1><antiPD1><anticancer immunotherapy><biological signal transduction><cancer evasion><cancer immune escape><cancer immune evasion><cancer immunotherapy><cancer in the colon><cancer metastasis><cancer microenvironment><cancer progression><cancer therapy><cancer-directed therapy><chimeras><colon cancer metastasis><colon cancer patients><colon cancer therapy><colon cancer treatment><colon neoplasia><colorectal cancer patients><colorectal neoplasia><design><designing><determine efficacy><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><gene expression analysis><gene expression assay><genome scale><genome-wide><genomewide><ifnar1 gene product><immune competent><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunotherapy for cancer><immunotherapy of cancer><in vivo><killer T cell><large bowel neoplasm><lipid based nanoparticle><lipid nanoparticle><liver metastases><lung metastasis><malignancy><malignant liver neoplasm, specified as secondary><metastasis in the liver><metastasis to the liver><metastasize to the liver><metastasize to the lung><metastatic cancer to liver><metastatic liver><metastatic liver neoplasm><mortality><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><ontogeny><pathway><patient derived xenograft model><patient response><patient specific response><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><promoter><promotor><protein death-ligand 1><pulmonary><pulmonary metastasis><reconstitute><reconstitution><recruit><resistant><response><responsive patient><scRNA-seq><secondary liver malignancy><secondary malignant liver neoplasm><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><social role><study design><systemic lupus erythematosus susceptibility 2><systemic toxicity><thymus derived lymphocyte><transcriptional profiling><tumor><tumor cell metastasis><tumor evasion><tumor growth><tumor immune evasion><tumor microenvironment><tumor progression><type I IFN receptor><type I interferon receptor><αPD-1><αPD1>