Document text
Principal Investigator: Yan-Ting Chen
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $50,474
Funding agency: National Cancer Institute
PROJECT SUMMARY/ ABSTRACT
Immune checkpoint blockade (ICB), aimed at reinvigorating immune cells such as T-cells, has exhibited clinical
success in a subset of patients yet fails to be applicable to many tumor subtypes. These unresponsive subtypes
upregulate gene signatures associated with amino acid (AA) metabolism and deprivation. However, how AA
deprivation contribute to poor ICB response remains unclear. Upon chronic antigen stimulation, T-cells become
“exhausted”, an alternative differentiation state that entails the loss of cytotoxic effector function and proliferative
capacity. T-cell exhaustion involves extensive transcriptomic and epigenetic remodeling; however, the loss of
cytokine production occurs despite adequate expression of transcripts encoding cytokines, suggesting post-
transcriptional mechanisms of restricting effector function within tumors. The long-term goal is to elucidate the
mechanisms underlying T-cell dysfunction within the tumor microenvironment and leverage these insights to
enhance ICB efficacy. The predoctoral research (Aim 1) will aim to investigate how local AA availability limits
effector function in tumor-infiltrating T-cells. Preliminary data showed that intratumoral T-cells can not engage in
efficient translation and they experience glutamine deprivation in the tumor microenvironment. Elevated
translational demand downstream of chronic T-cell receptor signaling cannot be met when extracellular AAs are
limiting, restricting both global translation rate and cytotoxic cytokine production. Specific Aim 1.1 will seek to
determine how local AA availability impacts the exhausted T-cell proteome. Nascent transcriptomic and
translatomic alterations will be profiled to evaluate the impact of AA limitation on gene-specific translation rates,
followed by ribosomal footprinting assays to identify cell state- and AA-dependent stalling in vivo. Specific Aim
1.2 will investigate the impact of enhancing AA availability on ICB. A broad-spectrum AA transporter will be
overexpressed in T-cells to examine whether it enhances tumor control in response to ICB and overcomes the
immunosuppressive effects conferred by cancer-associated fibroblasts via restricting intratumoral AA availability.
My postdoctoral research (Aim 2) will focus on the role of non-coding RNAs in translational suppression during
terminal T-cell exhaustion. I will profile how T-cell exhaustion impact the expression of non-coding RNAs and
examine whether non-coding RNA subsequently modulates translation and cytokine production. Overall, these
two projects will unveil the distinct mechanisms driving T-cell dysfunction through translational suppression
during early tumor-infiltration and late terminal exhaustion. The research and training plan outlined in this
proposal will be completed with the joint mentorship of Dr. Santosha Vardhana and Dr. Jayanta Chaudhuri at
Memorial Sloan Kettering Cancer Center (MSK). MSK’s top-notch cancer research environment and abundant
resources in conjunction with the support of the Gerstner Sloan Kettering Graduate School will guarantee the
successful completion of the proposed research and career development plans.
Terms: <Amino Acid Channel><Amino Acid Transport Systems><Amino Acid Transporter><Amino Acids><Antigens><Assay><Attenuated><Automobile Driving><Autoregulation><Bioassay><Biological Assay><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Patient><Cancers><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell-Mediated Lympholytic Cells><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular immunotherapy><Chronic><Clinical><Cytokine Suppression><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Development Plans><Development and Research><Dysfunction><Elements><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Exhibits><Failure><Fibroblasts><Functional RNA><Functional disorder><Gene Transcription><Genes><Genetic Transcription><Gln><Glutamine><Goals><Homeostasis><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Impairment><Individual><Infiltration><Inflammatory><Intervention><Intervention Strategies><Intrinsic factor><Joints><L-Glutamine><Lytotoxicity><MHC Receptor><MSKCC><Major Histocompatibility Complex Receptor><Malignant Neoplasms><Malignant Tumor><Mediating><Memorial Sloan-Kettering Cancer Center><Mentorship><Metabolic><Micronutrients><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nuclear><Nutrient><Patients><Physiological Homeostasis><Physiopathology><Play><Postdoc><Postdoctoral Fellow><Production><Protein Biosynthesis><Proteins><Proteome><Q Levoglutamide><Q. Levoglutamide><R & D><R&D><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Expression><Receptor Signaling><Research><Research Associate><Research Grants><Research Project Grants><Research Projects><Research Resources><Resistance><Resources><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomal RNA><Ribosomes><Role><Small RNA><Subcellular Process><T cell based therapeutics><T cell based therapy><T cell differentiation><T cell directed therapies><T cell response><T cell targeted therapeutics><T cell therapy><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><Teff cell><Training><Transcript><Transcription><Transfer RNA><Translations><Triplet Codon-Amino Acid Adaptor><Tumor Immunity><Tumor Subtype><Untranslated RNA><Up-Regulation><Upregulation><Work><adoptive T cell transfer><adoptive T-cell therapy><amino acid metabolism><aminoacid><anti-cancer research><anti-tumor immunity><antigen-specific T cells><antitumor immunity><attenuate><attenuates><cancer immunity><cancer infiltrating T cells><cancer microenvironment><cancer research><career development><cell-based immunotherapy><check point blockade><checkpoint blockade><chimeric antigen receptor><cytokine><cytotoxic><cytotoxicity><deprivation><driving><effector T cell><epigenetically><exhaust><exhaustion><experience><extracellular><gene signatures><genetic signature><graduate school><immune cell therapy><immune check point><immune check point blockade><immune checkpoint><immune checkpoint blockade><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunogen><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><insight><interventional strategy><killer T cell><mRNA Translation><malignancy><neoplasm/cancer><new approaches><noncoding><notch><notch protein><notch receptors><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><pathophysiology><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><post-doc><post-doctoral><post-doctoral trainee><posttranscriptional><pre-doc><pre-doctoral><predoctoral><protein synthesis><rRNA><research and development><research associates><resistant><response><social role><success><tRNA><therapeutic T-cell platform><thymus derived lymphocyte><transcriptomics><transfer Ribonucleic acids><translation><tumor><tumor infiltrating T cells><tumor microenvironment>