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Principal Investigator: Andrew Gunderson
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $404,798
Funding agency: National Cancer Institute
PROJECT SUMMARY
Tertiary lymphoid structures (TLS) are T and B lymphocytes in aggregation with antigen presenting cells,
fibroblasts, and high endothelial venules observed in some chronically inflamed tissues. TLS formation in tumors
of cancer patients is associated with improved adaptive immune function and increased overall survival. In
surgically resected human pancreatic ductal adenocarcinoma (PDAC), a significant proportion of patients form
spontaneous TLS in their primary tumors. Other groups have demonstrated similar findings, but no evidence
currently exists showing TLS directly influence T cell immunity. In this application we propose to investigate if
TLS enhance T cell immunity in the context of PDAC tumorigenesis and the mechanism of how this occurs. Our
preliminary data in TLS+ mouse and human PDAC tumors shows TCF1+ stem-like T cells (T-stem) are enriched
specifically within TLS relative to the surrounding tumor and stroma. We posit that TLS in PDAC tumors support
the development of stem-like T cell phenotypes (T-stem), dependent on interleukin-21 signaling. These unique
T cell subsets have previously been shown to sustain cellular immunity during chronic infection and cancer,
providing continual repletion of memory, effector, and terminally differentiated cells following antigenic recall or
immune checkpoint blockade treatment. We model this biology using a panel of mouse PDAC cell lines derived
from transgenic mouse tumors that conditionally express mutant KRas and p53, the most common driver
mutations in PDAC, and encode for a model MHCI-restricted antigen to track tumor antigen-specific responses.
These cancer cell lines, despite sharing a similar genetic and mutational background, induce tumors with unique
phenotypes and heterogenous tumor microenvironments. We will deploy a novel method to induce TLS in these
mouse tumors through lymphotoxin beta receptor (LTBR) agonism, whereby some of our mouse tumor lines are
permissive for TLS formation and others are resistant. We will test if the TLS-mediated generation of T-stem is
responsible for improved tumor control in CD8 conditional TCF1-knockout mice. We will determine if their
enrichment in TLS is due to IL-21 signals derived directly from TLS that promote their formation, independent of
lymphatic involvement, utilizing a combination of cell lineage tracing and genetically modified mouse models.
We will complement these studies by investigating tumor samples from PDAC patients for phenotypic pathways
unique to specific regions of these tumors. We will achieve this by performing spatial transcriptomics on human
PDAC tumor sections analyzed by an innovative algorithm that transforms spatial variable genes into functional
tissue modules to determine region-specific immune phenotypes localized to the TLS compared to non-TLS
regions and tumors without TLS. This approach identifies the mechanism of how TLS supports T cell function in
authentic mouse models of TLS+ PDAC and translates these findings to human cancer patients so novel
immunotherapy options designed to elicit and activate TLS can be offered to patients with a treatment resistant
malignancy.
Terms: <Ablation><Address><Adoptive Transfer><Agonist><Algorithms><Anti-CD40><Antibodies><Antigen-Presenting Cells><Antigens><Antioncogene Protein p53><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Biological Function><Biological Process><Biology><Blood><Blood Reticuloendothelial System><Body Tissues><CD44><CD44 gene><CD62L><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><Cancer Patient><Cancer cell line><Cancers><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Line><Cell Lineage><Cell Mediated Immunology><Cell Physiology><Cell Process><Cell Signaling><Cell-Mediated Immunity><CellLine><Cells><Cellular Function><Cellular Immune Function><Cellular Immunity><Cellular Physiology><Cellular Process><Cellular Tumor Antigen P53><Chimera Protein><Chimeric Proteins><Chronic><Collaborations><Complement><Complement Proteins><Data><Development><Ectopic lymphoid organ><Ectopic lymphoid structure><Fc Receptor><Fibroblasts><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fourier Transform><Frequencies><Fusion Protein><Gene Modified><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Germinal Center><Graph><HLHRC><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><High Endothelial Venule><Human><IL-21 receptor><IL21><IL21R><Immune><Immune Cell Activation><Immune mediated therapy><Immune memory><Immune reaction><Immunes><Immunity><Immunochemical Immunologic><Immunofluorescence><Immunofluorescence Immunologic><Immunologic><Immunologic Memory><Immunological><Immunological Memory><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><In Situ><Inducer Cells><Inducer T-Lymphocytes><Intracellular Communication and Signaling><KO mice><KRAS driven oncogenesis><KRAS oncogenesis><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><Knock-out Mice><Knockout Mice><LAM-1 gene><LECAM1><LNHR><LSEL><LYAM-1><LYAM1><LYT3><LoxP-flanked allele><Luciferase Immunologic><Luciferases><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic><Lymphatic nodes><MDU3><Maintenance><Malignant Neoplasms><Malignant Tumor><Mediating><Memory><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><Null Mouse><Oncogenesis><Oncoprotein p53><Operative Procedures><Operative Surgical Procedures><P53><PD 1><PD-1><PD1><PDAC cancer cell><PDAC cell><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Pathway interactions><Patients><Peripheral><Pgp1><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Primary Neoplasm><Primary Tumor><Protein TP53><Publishing><Reaction><Reporter><Reporting><Research><Resected><Residencies><Resistance><Role><SELL gene><SIYRYYGL><Sampling><Selectin L Gene><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Spleen><Spleen Reticuloendothelial System><Strains Cell Lines><Structure of germinal center of lymph node><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><T cell differentiation><T cell response><T memory cell><T-Cell Activation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><TP53><TP53 gene><TQ-1><TRP53><Teff cell><Tertiary lymphoid structure><Testing><Time><Tissues><Transgenic Mice><Translating><Tumor Antigens><Tumor Immunity><Tumor Promotion><Tumor Protein p53><Tumor Protein p53 Gene><Tumor-Associated Antigen><Work><aPD-1><aPD1><accessory cell><activate T cells><anamnestic reaction><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-programmed cell death protein 1><anti-tumor immunity><antiPD-1><antiPD1><antibody receptor><antitumor immunity><biological signal transduction><cancer antigens><cancer immunity><cancer microenvironment><cancer type><cellular differentiation><check point blockade><checkpoint blockade><chronic infection><complementation><computational framework><computer framework><cultured cell line><design><designing><developmental><draining lymph node><driver lesion><driver mutation><effector T cell><flow cytophotometry><floxed><floxed allele><gene modification><gene signatures><genetic signature><genetically modified><genome mutation><immune activation><immune check point blockade><immune checkpoint blockade><immune function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunoreaction><implantation><improved><innovate><innovation><innovative><insight><interleukin-21><interleukin-21 receptor><lymph gland><lymph nodes><lymphnodes><lymphotoxin beta receptor><lymphotoxin β receptor><lymphotoxin-beta-specific receptor><malignancy><memory T lymphocyte><mouse model><multidisciplinary><murine model><mutant><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><novel><oncogenic KRAS><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pancreatic ductal adenocarcinoma cell><pancreatic neoplasia><pancreatic neoplasm><pathway><permissiveness><persistent infection><pre-clinical><preclinical><predict responsiveness><predicting response><prognostic><prognostic of overall survival><prognostic of survival><programmed cell death 1><programmed cell death protein 1><programmed death 1><protein p53><regional lymph node><resistant><response><secondary immune response><sle2><social role><stem><surgery><survival prognosis><systemic lupus erythematosus susceptibility 2><tertiary lymphoid organ><thymus derived lymphocyte><tissue biomarkers><transcriptomics><tumor><tumor growth><tumor microenvironment><tumor-specific antigen><tumorigenesis><αPD-1><αPD1>