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Principal Investigator: CHENGCHENG ZHANG
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $551,973
Funding agency: National Cancer Institute
Abstract
T cell-centered immunotherapies, including PD-1/PD-L1 blockade, have been successful
in treating some types of cancers but not others. The roles of other immune cells including
immunosuppressive monocytic cells in tumor development and treatment are not well
defined. A better understanding of the molecular regulation of signaling and function of
these monocytic cells will support development of novel therapeutic strategies for cancer
treatment. The leukocyte Ig-like receptor subfamily B (LILRB) proteins are a group of type
I transmembrane glycoproteins with extracellular Ig-like domains that bind ligands and
intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that can recruit
tyrosine phosphatases SHP1, SHP2, or the inositol-phosphatase SHIP. We have been
investigating the roles of this family of immune checkpoint receptors in tumor
development. We demonstrated that several ITIM-receptors including LILRB2, LILRB4,
and a related receptor LAIR1 support leukemia development. As the most restrictively
expressed member of the LILRB family, LILRB4 is mainly expressed on monocytic cells
but not on stem cells or progenitors. We and others further demonstrated that LILRB4 is
a surface marker for monocytic AML and monocytic myeloid-derived suppressor cells.
Importantly, we elucidated two novel functions of LILRB4: it supports infiltration of
malignant monocytic cells and relieves immune inhibition of T cells. Furthermore, we
developed anti-LILRB4 blocking antibodies and CAR-T cells that efficiently inhibit
monocytic leukemia development in various mouse models including humanized and
patient-derived xenografted mice. Here, based on new preliminary results, we propose the
following Aims to test the hypothesis that the expression and signaling of LILRB4 in
immunosuppressive monocytic cells support tumor development. In Aim 1, we will
determine the function of LILRB4 signaling in immunosupressive monocytic cells and
whether LILRB4 blocking/targeting inhibits tumor development. We will then determine
how LILRB4 expression is transcriptionally regulated by extrinsic factors in Aim 2. Finally
we will determine whether the DNA sensor protein Absent In Melanoma 2 (AIM2) is a key
downstream effector of LILRB4 signaling in Aim 3. Our study will provide important
mechanistic insights into immune checkpoint biology and directly guide the development
of novel immunotherapies for cancer treatment.
Terms: <AIM2 gene><Absent in Melanoma 2><Antibodies><Binding Site Domain><Biology><Blocking Antibodies><Blood leukocyte><Blood monocyte><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><Calciol><Cancer Patient><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Surface Glycoproteins><Cells><Chiro-Inositol><Cholecalciferol><Collaborations><Coupled><DNA><Deoxyribonucleic Acid><Development><Endocrine Gland Secretion><Family><Gene Transcription><Genetic Transcription><Goals><HCPH><Hematopoietic Cell Phosphatase><Hormones><Human><ITIM><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunology><Immunoreceptor Tyrosine-Based Inhibitory Motif><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Infiltration><Inflammasome><Innate Immunity><Inositol><Intracellular Communication and Signaling><Leukocytes><Leukocytes Reticuloendothelial System><Ligand Binding Domain><Malignant><Malignant - descriptor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Marrow leukocyte><Marrow monocyte><Mediator><Membrane Glycoproteins><Mesoinositol><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Monocytic leukemia><Murine><Mus><Myeloid-derived suppressor cells><Native Immunity><Natural Immunity><Non-Receptor Type 11 Protein Tyrosine Phosphatase><Non-Specific Immunity><Nonreceptor Type 6 Protein-Tyrosine Phosphatase><Nonspecific Immunity><PD-1/PD-L1><PD-1/PDL1><PD-L1 blockade><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDL1 blockade><PDX model><PTP-1C><PTP-2 enzyme><PTP1C><PTP2C><PTPN11><PTPN11 gene><PTPN6><PTPN6 gene><Patient derived xenograft><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Play><Progenitor Cells><Protein Tyrosine Phosphatase 2C><Protein-Tyrosine Phosphatase 1C><Protein-Tyrosine Phosphatase 2C><Proteins><RNA Expression><Receptor Protein><Regulation><Role><SHP-1><SHP2><SHP2 Phosphatase><SHPTP2><Schilling's leukemia><Shp-2 tyrosine phosphatase><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Supporting Cell><Surface><Surface Glycoproteins><T cells for CAR><T-Cells><T-Lymphocyte><Testing><Texas><Therapeutic><Therapeutic Hormone><Transcription><Tyrosine Phosphatase SHP2><Tyrosine phosphatase SHP1><Up-Regulation><Upregulation><VIT D><VitD3><Vitamin D><Vitamin D 3><Vitamin D3><White Blood Cells><White Cell><anti-PD-L1 blockade><anti-cancer immunotherapy><anti-cancer therapy><anticancer immunotherapy><biological signal transduction><cancer immunotherapy><cancer invasiveness><cancer therapy><cancer type><cancer-directed therapy><check point receptors><checkpoint receptors><chimeric antigen T cell 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><developmental><extracellular><gain of function><immune check point><immune checkpoint><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunosuppressive activity><immunosuppressive function><immunosuppressive myeloid cells><immunosuppressive response><immunotherapy for cancer><immunotherapy of cancer><in vivo><insight><leukemia><loss of function><malignancy><member><migration><monocyte><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplasm/cancer><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><patient derived xenograft model><progenitor><receptor><recruit><sensor><social role><stem cells><suppressive myeloid cells><thymus derived lymphocyte><tumor><tumorigenic><white blood cell><white blood corpuscle>