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Principal Investigator: Lawrence P. Kane
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $66,992
Funding agency: National Cancer Institute
PROJECT SUMMARY
Activated CD8+ T cells are capable of responding to tumor neoantigens and can aid in the clearance of tumors.
Indeed, CD8+ T cells are critical for the beneficial effects of immune checkpoint blockade therapies, in those
patients that respond to such therapies (mAb’s to CTLA-4, PD-1/L1, LAG3). In addition, CD8+ T cells themselves
can be deployed as therapies, in the form of CAR-T cells for some hematological malignancies. Other therapeutic
or preventative modalities still under active study include expansion and infusion of tumor-infiltrating lymphocytes
(TIL) and vaccination. All of these approaches require either the presence of tumor specific CD8+ T cells whose
function can be augmented or knowledge about a tumor neoantigen that can be directly targeted therapeutically.
Despite advances, there are still significant gaps in knowledge regarding how tumor-specific CD8+ T cells are
primed, how they are recruited to (or excluded from) the tumor, and how they become dysfunctional in the tumor
microenvironment.
Our understanding of the rules of T cell development, function and antigen discrimination have been greatly
enhanced using T cell receptor transgenic (TCR Tg) mice. These models provide a traceable pool of antigen-
specific T cells that can be studied over the course of an infection. Many investigators have also taken advantage
of TCR Tg T cells to model responses to tumor antigens, by expressing the cognate antigen (e.g. LCMV GP,
OVA) in transplantable tumor lines or genetic tumor models. One of the limitations of such studies is that they
have mostly employed non-tumor antigens and their respective TCR’s, which often represent high affinity outlier
TCR-ligand pairings. There is thus a need for additional models that employ naturally arising tumor neo-antigens
and matching TCR’s.
One of the most commonly used transplantable murine syngeneic tumor lines in the C57BL/6 background is
MC38, a colon carcinoma model originally derived from C57BL/6 mice treated with methylcholanthrene. A recent
study reported the identification of a tumor neo-antigen in the MC38 model, a mutated form of the ribosomal
protein Rpl18, referred to hereafter as Rpl18*, presented by H-2Kb. We have now validated that this represents
a major T cell epitope in C57BL/6 mice bearing MC38 tumors. We have also identified TCR’s that recognize this
epitope and confirmed that these TCR’s can mediate T cell activation and effector function. We now propose to
use two of the TCR’s that we have identified to generate TCR Tg mouse lines that can be used for future study
of T cell anti-tumor responses in mouse models.
Terms: <Affinity><Antigenic Determinants><Antigens><Antitumor Response><Assay><Bacteria><Binding><Binding Determinants><Bioassay><Biological Assay><C57BL/6 Mouse><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><CD152><CD152 Antigen><CD152 Gene><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><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancers><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Clinical Research><Clinical Study><Clinical Treatment Moab><Cognitive Discrimination><Colon Cancer><Colon Carcinoma><Core Facility><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Discrimination><Epitopes><Exclusion><Future><Genetic><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hybridomas><Immune><Immune response><Immune system><Immunes><Immunological response><In Vitro><Individual><Infection><Infiltration><Infusion><Infusion procedures><Investigators><Knowledge><LCM Viruses><LCMV><LYT3><Ligands><Lymphocytic choriomeningitis virus><Lytotoxicity><MC-38><MC38><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Tumor><Mediating><Methylcholanthrene><Mice><Mice Mammals><Modality><Modeling><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Mutate><Neoplasm Transplantation><Ovum><PD 1><PD-1><PD1><Patients><Peptides><Physiologic pulse><Play><Population><Proliferating><Pulse><Reporting><Research Personnel><Researchers><Ribosomal Proteins><Role><Sensitivity and Specificity><T cell response><T cells for CAR><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Development><T-Cell Epitopes><T-Cell Ontogeny><T-Cell Receptor><T-Cells><T-Lymphocyte><T-Lymphocyte Development><T-Lymphocyte Epitopes><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Transgenes><Transgenic Mice><Transplantation><Tumor Antigens><Tumor Cell><Tumor-Associated Antigen><Tumor-Infiltrating Lymphocytes><Unfertilized Egg><Vaccination><Viral Diseases><Virus><Virus Diseases><activate T cells><anti-tumor response><antigen-specific T cells><cancer antigens><cancer in the colon><cancer microenvironment><check point blockade><checkpoint blockade><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><cytotoxic T-lymphocyte antigen 4><cytotoxicity><egg/ovum><engineered T cells><fighting><fungus><genetically engineered T-cells><host response><immune check point blockade><immune checkpoint blockade><immune system response><immunogen><immunoresponse><infusions><mAbs><malignancy><monoclonal Abs><mouse model><murine model><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><neoplastic cell><novel><pre-clinical study><preclinical study><programmed cell death 1><programmed cell death protein 1><programmed death 1><recruit><response><sle2><social role><success><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><transgene><transgenic T- cells><transplant><tumor><tumor microenvironment><tumor transplant><tumor transplantation><tumor-specific antigen><viral infection><virus infection><virus-induced disease><weapons>