Rewiring the myeloid cell response to adjuvants to improve tumor control

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Principal Investigator: Michael James Gough
Organization: PROVIDENCE PORTLAND MEDICAL CENTER
Fiscal Year: 2024
Award: $358,566
Funding agency: National Cancer Institute

The critical preliminary data for this proposal is that contrary to the accepted dogma, following exposure to
endogenous immune adjuvants MyD88 delivers a negative signal to macrophages that limits tumor control by
radiation therapy. We demonstrate that in poorly immunogenic tumors, macrophages are rewired following
exposure to dying cancer cells such that they suppress multiple features of the tumor immune environment.
This includes the ability of T cells to control residual disease, and dendritic cell maturation. The aim of this
proposal is to understand the mechanisms by which this suppression occurs, identify the regulation of
macrophage suppression, and use this to identify patient populations that will respond poorly to current
therapies. We hypothesize that exposure to dying cells rewires macrophage signaling such that innate
activation of MyD88 suppresses local tumor immunity. The specific aims of this study are to 1: Test the
hypothesis that loss of MyD88 prevents NFKB driven-anti-inflammatory gene transcription and results in
increased IRF3 driven IFN transcription; 2: Test the hypothesis that signaling through Mertk-mediated ‘rewiring’
of macrophages changes the response to adjuvants limiting immune function in the tumor environment; and 3:
Test the hypothesis that MyD88 patterns of gene expression are linked to poor patient outcome. Our study
design incorporates CT-guided radiation therapy of multiple authentic pancreatic tumor models and using a
range of RT doses and fractionations. These are combined with unique knockouts and assays that allow us to
identify divergent myeloid responses in vitro and in vivo. Our analyses of clinical samples use high quality
bioinformatic approaches that allow us to evaluate effect of the tumor environment on the biological response
to innate adjuvants in patient samples.

Terms: <Adjuvant><Amphoterin><Amphoterin Gene><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoptotic><Assay><Bio-Informatics><Bioassay><Bioinformatics><Biological><Biological Assay><Cancers><Cell Body><Cell Communication and Signaling><Cell Maturation><Cell Signaling><Cells><Cellular Immune Function><Cessation of life><Chemical Fractionation><Chemotherapy and Radiation><Chemotherapy and/or radiation><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><Clinical><Collection><Cross Presentation><Cytotoxic Chemotherapy><Cytotoxic Therapy><Data><Data Set><Death><Dendritic Cells><Detectable Residual Disease><Dose><Environment><Exposure to><Expression Signature><FM1 Gene Product><FRACN><Failure><Fractionation><Fractionation Radiotherapy><Gene Expression Profile><Gene Transcription><Genes><Genetic Transcription><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><Heat shock proteins><Heparin-Binding Protein p30><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><IFN><IFN-regulatory factor 3><IRF-3 protein><IRF3><IRF3 gene><Immune><Immune mediated therapy><Immunes><Immunity><Immunoactivators><Immunoadjuvants><Immunoglobulin Enhancer-Binding Protein><Immunologic Adjuvants><Immunologically Directed Therapy><Immunopotentiators><Immunostimulants><Immunotherapy><In Vitro><Inflammatory><Interferon Regulatory Factor 3><Interferons><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knock-out><Knockout><Link><Macrophage><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mediating><Minimal Residual Disease><Myelogenous><Myeloid><Myeloid Cells><Mφ><NF-kB><NF-kappa B><NF-kappaB><NFKB><Necrosis><Necrotic><Non-Polyadenylated RNA><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Outcome><Pancreas><Pancreas Cancer><Pancreatic><Pancreatic Cancer><Pathologic><Pathology><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pre-Clinical Model><Preclinical Models><Process><RNA><RNA Expression><RNA Gene Products><Radiation therapy><Radiotherapeutics><Radiotherapy><Regulation><Research Design><Residual Neoplasm><Residual Tumors><Ribonucleic Acid><SBP-1><SBP-1 Gene><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Stimulator of Interferon Genes><Study Type><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><T cell response><T-Cells><T-Lymphocyte><TLR protein><Testing><Therapeutic><Toll-Like Receptor Family Gene><Toll-like receptors><Transcription><Transcription Factor NF-kB><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Treatment Failure><Tumor Biology><Tumor Immunity><Tumor-associated macrophages><Veiled Cells><anti-tumor immunity><antitumor immunity><biologic><biological signal transduction><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer cell><cancer immunity><cancer type><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><cyclic GMP-AMP synthase/STING><environment enrichment><environment enrichment for laboratory animals><environmental enrichment><environmental enrichment for laboratory animals><extranuclear DNA><gene expression pattern><gene expression signature><immune check point therapy><immune checkpoint therapy><immune function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenic><improved><improved outcome><in vivo><interventional strategy><kappa B Enhancer Binding Protein><malignancy><neoplasm/cancer><novel><nuclear factor kappa beta><pancreatic cancer model><pancreatic malignancy><pancreatic tumor model><patient oriented outcomes><patient population><patient response><patient specific response><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><prevent><preventing><radiation or chemotherapy><radiation treatment><residual disease><response><responsive patient><sensor><stress protein><study design><success><therapy failure><thymus derived lymphocyte><transcriptional profile><transcriptional signature><treatment with radiation><tumor>