Interplay of natural killer cells and extracellular matrix proteins in solid cancers
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Principal Investigator: Shadmehr Demehri Organization: MASSACHUSETTS GENERAL HOSPITAL Fiscal Year: 2024 Award: $660,987 Funding agency: National Cancer Institute Project Summary/Abstract: Natural killer (NK) cells have long been known to provide critical early defense against viral infections and malignancies. Nevertheless, most of the clinical success associated with using NK cells has been restricted to hematological malignancies, which can be partly attributed to the defective NK cell activation in peripheral tissues. Extracellular matrix (ECM) proteins are present in all peripheral tissues where they maintain homeostasis by providing scaffold as well as important developmental cues to the surrounding cells. We have recently discovered a critical role for ECM proteins in switching the function of conventional NK cells as they exit the circulation and enter the peripheral tissues. We aim to investigate how ECM proteins regulate NK cell functions in the skin and solid cancers. Skin and breast cancer are the leading cause of cancer morbidity and mortality in the United States. These cancers frequently develop primary and secondary resistance to current immunotherapeutics. In addition, chemotherapies for them cause wide-ranging side effects and thus significantly burden the health care system. Defective ECM turnover is a hallmark of skin, breast, and other solid cancers. To fully elucidate the bi-directional interactions between NK cells and ECM in the context of solid cancer development, we aim to (1) Determine the mechanism of collagen-induced loss of NK cell killing function in solid cancers, (2) Determine the role of collagen-III in the regulation of NK cell helper function in solid cancers, and (3) Examine the impact of other major ECM proteins on NK cell functionality. The outcomes of the proposed studies will reveal novel mechanisms of ECM-NK cell interactions in cancer. Our research will greatly facilitate the development of novel therapeutic strategies to harness NK cells for the treatment of solid cancers. Terms: <7-Transmembrane Protein with no EGF-Like N-Terminal Domains1><ADGR1><ADGR1 gene><Ab-dependent cellular cytotoxicity><Antibodies><Assay><Autoregulation><Bioassay><Biological Assay><Blocking Antibodies><Body Tissues><Breast><Breast Cancer><Breast Melanoma><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Cause><Cancer Etiology><Cancers><Cas nuclease technology><Cell Body><Cell Communication><Cell Function><Cell Interaction><Cell Physiology><Cell Process><Cell-Extracellular Matrix><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemotactic Cytokines><Circulation><Clinical><Closure by Ligation><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cold-Insoluble Globulins><Collagen><Collagen Receptors><Cues><Cytotoxic cell><Data><Dendritic cell activation><Deposit><Deposition><Development><ECM><ECM receptor><Effector Cell><Elastin><Engineering><Exposure to><Extracellular Matrix><Extracellular Matrix Proteins><FN1><Fibronectin 1><Fibronectins><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><G Protein-Coupled Receptor 56><GPR56><Glycoprotein GP-2><Goals><Health Care Systems><Healthcare Systems><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Homeostasis><Homologous Chemotactic Cytokines><Human><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Surveillance><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunity><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunologic Surveillance><Immunologic Surveillances><Immunological Diseases><Immunological Dysfunction><Immunological Surveillance><Immunological Surveillances><Immunological System Dysfunction><Immunological response><Immunosurveillance><Immunotherapeutic agent><In Vitro><Inducer Cells><Inducer T-Lymphocytes><Infiltration><Integrins><Integrins Extracellular Matrix><Intercrines><K Cells><K lymphocyte><Killer Cells><Knock-out><Knockout><LETS Proteins><Laboratories><Laminin><Large External Transformation-Sensitive Protein><Ligands><Ligation><Lytotoxicity><Malignant Breast Neoplasm><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Mediating><Modeling><Modern Man><Morbidity><Morbidity - disease rate><NK Cell Activation><NK Cells><NK cell therapy><Natural Killer Cell Activation><Natural Killer Cells><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Outcome><Outcomes Research><Peripheral><Phenotype><Physiological Homeostasis><Play><Production><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Regulation><Research><Resistance><Role><SIS cytokines><Skin><Skin Cancer><Solid><Subcellular Process><System><T-Cells><T-Lymphocyte><TM7XN1><Testing><Tissues><United States><Viral Diseases><Virus Diseases><Work><Xenograft Model><adaptive immunity><alpha 2-Surface Binding Glycoprotein><anti-tumor immune response><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular cytotoxicity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><cancer microenvironment><cell killing><chemoattractant cytokine><chemokine><chemotherapy><cytokine><cytotoxicity><developmental><elastin receptor><elastin receptor complex><elastin-binding protein><extracellular matrix receptor><flow cytophotometry><gene editing method><gene editing methodology><gene editing strategy><gene editing techniques><gene-editing approach><healthcare burden><host response><immune drugs><immune system response><immune-based therapeutics><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><improved><malignancy><malignant breast tumor><malignant skin tumor><mortality><mouse model><murine model><natural killer cell therapy><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><programs><receptor><recruit><resistant><response><scaffold><scaffolding><side effect><social role><success><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><tumor><tumor microenvironment><viral infection><virus infection><virus-induced disease><xenograft transplant model><xenotransplant model>