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Principal Investigator: Shayna Thomas-Jardin
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $76,756
Funding agency: National Cancer Institute
PROJECT SUMMARY
In recent years, there have been groundbreaking discoveries in the identification and therapeutic targeting of
the PD-1/PD-L1 immune checkpoint axis. Lung cancer cells express high levels of Programmed Death Ligand
1 (PD-L1), a critical ligand for PD-1 on T cells. The PD-1/PD-L1 interaction allows tumor cells to directly
suppress anti-tumor T cell activity, resulting in immune escape and tumor progression. Despite these
advances, there remains a disconnect in patient expression of PD-L1 and treatment response. This
underscores the critical need to understand mechanisms of PD-L1 upregulation, identify mechanisms of
resistance to PD-1/PD-L1 therapy, and identify other immune checkpoints or pathways to pursue clinically in
combination with this therapy. In response to tumor microenvironment stresses, such as hypoxia, heme
deprivation, and amino acid starvation, cancer cells activate the integrated stress response (ISR). ISR
activation allows cancer cells to escape these stresses through inhibition of global protein synthesis and
increased translation of select mRNAs. The ISR has been shown to promote tumorigenesis, yet the role of the
ISR in the translational control of immune checkpoint proteins has not been fully investigated. We recently
demonstrated that ISR activation leads to potent induction of PD-L1 in non-small cell lung cancer (NSCLC) and
suppression of anti-tumor immunity in vitro and in vivo, and we have new evidence that another immune
checkpoint, CD155 (Cluster of differentiation 155), is induced upon ISR activation in NSCLC cells
simultaneously with PD-L1. Our central hypothesis is that ISR activation causes tumor cell immune escape
through translation of both PD-L1 and CD155. Guided by strong preliminary data, we will test this hypothesis
by pursuing three specific aims: 1) Elucidate the mechanisms through which ISR activation promotes
translation of CD155; 2) Determine the effect of ISR modulation on immune cell responses; 3) Examine the
therapeutic efficacy of ISR inhibition in combination with PD-1 blockade and/or TIGIT (CD155’s immune cell
receptor) blockade in mouse models. We will employ translational studies including luciferase reporter assays
and ribosome profiling to dissect the mechanisms of ISR mediated PD-L1 and CD155 translational control in
NSCLC cells. To determine the impact of ISR activation on immune cell responses, we will measure immune
cell responses in co-culture studies and immunocompetent mouse models upon ISR activation. Finally, we will
utilize mouse models and ISR inhibitors to determine whether ISR inhibition can suppress tumorigenesis by
promoting an immune response and whether this can synergize with existing immune checkpoint therapies
(Fig 1, model). Our proposed research is significant, because it will 1) uncover new regulatory circuits that
govern immune checkpoint protein expression, 2) illuminate how insults experienced by cancer cells in the
tumor microenvironment modulate the responses of immune cells, and 3) our studies will provide proof-of-
concept for the development of new combination therapies for lung cancer.
Terms: <5' Untranslated Regions><5'UTR><Amino Acids><Assay><B7-H1><B7H1><Bioassay><Biological Assay><CD274><Cancer Cause><Cancer Etiology><Cancer Patient><Cancers><Cell Body><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Surface Glycoproteins><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cessation of life><Clinical><Clinical Treatment Moab><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cytotoxic cell><Data><Death><Dendritic Cells><Development><ER stress><Environment><Eukaryotic Initiation Factors><Eukaryotic Peptide Initiation Factors><Eukaryotic Translation Initiation Factors><Ferroprotoporphyrin><Heme><Hypoxia><Hypoxic><IF2 Protein><ITIM><Immune><Immune Cell Suppression><Immune response><Immunes><Immunocompetent><Immunological response><Immunoreceptor Tyrosine-Based Inhibitory Motif><In Vitro><Initiation Factor-2><K lymphocyte><Kinases><Ligands><Luciferase Immunologic><Luciferases><Lung><Lung Respiratory System><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Measures><Mediating><Mediator><Membrane Glycoproteins><Messenger RNA><Mice><Mice Mammals><Modeling><Monoclonal Antibodies><Murine><Mus><NK Cells><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Natural Killer Cells><Nature><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><ORFs><Oncogenesis><Oncogenic><Open Reading Frames><Osmosis><Outcome><Oxygen Deficiency><PD 1><PD-1><PD-1 blockade><PD-L1><PD1><PD1 blockade><PDL-1><PDL1><Pathway interactions><Patients><Peptide Initiation Factor 2><Peptide Initiation Factor IF-2><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Population><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Prokaryotic Initiation Factor-2><Protein Biosynthesis><Protein Coding Region><Protein Phosphorylation><Proteins><Protoheme><Pulmonary Cancer><Pulmonary malignant Neoplasm><Receptor Cell><Receptor Protein><Recurrence><Recurrent><Regulation><Reporter><Research><Ribo-seq><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Role><Solid Neoplasm><Solid Tumor><Starvation><Stimulus><Stress><Subcellular Process><Surface Glycoproteins><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><Testing><Therapeutic><Translational Initiation Factor 2><Translations><Transphosphorylases><Treatment Efficacy><Tumor Cell><Tumor Immunity><Tumor Promotion><Tumor-infiltrating immune cells><Up-Regulation><Upregulation><Veiled Cells><Work><aminoacid><anti-PD-1 blockade><anti-PD1 blockade><anti-tumor immunity><antitumor immunity><arm><biological adaptation to stress><cancer cell><cancer immunity><cancer microenvironment><cancer progression><check point blockade><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><deprivation><developmental><endoplasmic reticulum stress><experience><ferroheme><fitness><heme biosynthesis><host response><humanized mice><humanized mouse><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point><immune check point blockade><immune check point therapy><immune checkpoint><immune checkpoint blockade><immune checkpoint therapy><immune competent><immune system response><immunecheckpoint><immunoresponse><in vivo><infB Gene Product><infB Protein><infiltration of tumors by immune cells><inhibitor><intervention efficacy><intratumoral immune cell><intratumoral immune infiltrate><lung cancer><lung cancer cell><mAbs><mRNA><mRNA Leader Sequences><malignancy><monoclonal Abs><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new combination therapies><pathway><polysome profiling><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><protein expression><protein synthesis><pulmonary><reaction; crisis><receptor><resistance mechanism><resistance to therapy><resistant mechanism><resistant to therapy><response><response to therapy><response to treatment><ribosome footprint profiling><ribosome profiling><sle2><social role><stress response><stress; reaction><synergism><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic resistance><therapeutic response><therapeutic target><therapy efficacy><therapy resistant><therapy response><thymus derived lymphocyte><translation><translational study><treatment resistance><treatment response><treatment responsiveness><tumor><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><tumor microenvironment><tumor progression><tumorigenesis>