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Principal Investigator: Chi Li
Organization: UNIVERSITY OF LOUISVILLE
Fiscal Year: 2023
Award: $219,491
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Lung cancer is a prevalent disease and consume many lives every year. Disease relapse, invasion and
metastases are the main causes of death. Recent discoveries provide compelling evidence that at least some
types of cancer are initiated and maintained by a small population of malignant cells called cancer-initiating
stem cells (CICs). Relapse, invasion, and metastases are explained by the fact that CICs have a different
biology than all the other tumor cells and, importantly, are resistant to chemotherapies and radiation. Lung
CICs have been shown to represent about 1–15% of all tumor cells and can form tumors with injections as low
as 100 cells. Evidence from published studies have demonstrated that human, as well as rodent, cancers
contain populations of cells that express embryonic stem (ES) cell antigens. Cells containing these proteins
also express markers used to identify lung CICs; therefore, we hypothesized that ES cells and CICs share
several common molecular traits. To test this hypothesis, we vaccinated mice with exosomes derived from ES
cells expressing GM-CSF and investigated whether an anti-tumor immune response was elicited. We
discovered that ES cell-derived exosome-based vaccination strategy (ES-exo vaccine) is very effective in
preventing both implantable and carcinogen-induced lung adenocarcinoma development without any
detectable toxicity or signs of autoimmunity. Recently published results from our laboratory reveal that
splenocytes from ES cell-immunized mice are preferentially cytotoxic to lung CICs. Experiments proposed in
this application seek to expand these novel findings to convincingly demonstrate that ES-exo vaccine
immunize against lung cancer-associated CICs and that anti-CIC immunity is responsible for preventing lung
adenocarcinoma development. The anti-tumor activities of ES-exo vaccine as well as their immunostimulatory
properties will be investigated in in vitro and in vivo lung cancer mouse models. Experiments proposed in this
study will address the translational potential of our novel ES-exo vaccine as a cell-free prophylactic vaccine
modality in implantable, transgenic and xenograft mouse models of lung cancer. One of the major goals of this
application is to identify tumor antigens important for anti-lung cancer efficacy of ES-exo vaccine using a
proteomics-based screening methodology. To fulfill the stated objectives, the following aims are proposed: 1)
Investigate whether lung cancer-initiating cells are targets of ES cell-derived exosomes (ES-exo) vaccination-
induced anti-tumor immunity, and 2) Evaluate the translational potential of ES cell-derived exosomes (ES-exo)
as a novel cell-free vaccine for lung cancer. Our proposed study will provide important insights towards
developing a safe prophylactic vaccine for lung cancer onset and/or recurrence.
Terms: <21+ years old><Address><Adenocarcinoma><Adjuvant><Adult><Adult Human><Age Months><Allogenic><Antigens><Antineoplastic Vaccine><Autoimmune Status><Autoimmunity><Binding><Biology><Body Tissues><CD34><CD34 gene><CD8><CD8B><CD8B1><CD8B1 gene><Cancer Biology><Cancer Cause><Cancer Causing Agents><Cancer Etiology><Cancer Patient><Cancer Treatment><Cancer Vaccines><Cancers><Carcinogens><Cause of Death><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cells><Cellular Proliferation><Cessation of life><Chemotherapy and Radiation><Chemotherapy and/or radiation><Consumption><Data><Daughter><Death><Development><Disease><Disorder><Dysembryoma><ES cell><Embryo><Embryonic><Fibroblasts><GM-CSF><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Granulocyte-Macrophage Colony-Stimulating Factor><Growth><HPCA1><Health><Health Care Costs><Health Costs><Healthcare Costs><Heterograft><Heterologous Transplantation><Histamine-Producing Cell-Stimulating Factor><Human><Immune><Immune response><Immunes><Immunity><Immunization><Immunize><Immunologic Subtyping><Immunological response><Immunophenotyping><Implant><In Vitro><Injections><Invaded><KRAS(G12D)><KRASG12D><LYT3><Laboratories><Lewis Lung Carcinoma><Life><Lung Adenocarcinoma><Lung Neoplasms><Lung Tumor><Malignant Adenoma><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Membrane><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methodology><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modality><Modern Man><Molecular><Molecular Interaction><Molgramostin><Murine><Mus><Mutation><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neoplasm Metastasis><Neoplasm Vaccines><Neoplastic Colony-Forming Units><Neoplastic Stem Cells><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonsmall Cell Lung Carcinoma><Oncogens><PDX model><Patient derived xenograft><Population><Preventative vaccine><Preventive vaccine><Progenitor Cells><Proliferating><Property><Prophylactic vaccine><Proteins><Proteomics><Publishing><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><Recurrence><Recurrent><Recurrent disease><Relapse><Relapsed Disease><Reporting><Resistance><Risk><Rodent><Rodentia><Rodents Mammals><Secondary Neoplasm><Secondary Tumor><Solid Neoplasm><Solid Tumor><Source><Specificity><Splenocyte><TC-GM-CSF><Teratoid Tumor><Teratoma><Testing><Tissue Growth><Tissues><Toxic effect><Toxicities><Transgenic Organisms><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor Stem Cells><Tumor Vaccines><Tumor-Associated Antigen><Tumor-Cell Human GM Colony-Stimulating Factor><Tumor-infiltrating immune cells><Vaccinated><Vaccination><Vaccines><Validation><Vesicle><Work><Xenograft><Xenograft procedure><Xenotransplantation><adulthood><anti-cancer><anti-cancer therapy><anti-tumor effect><anti-tumor immune response><anti-tumor immunity><anti-tumor vaccine><anticancer><anticancer therapy><antitumor effect><antitumor immune response><antitumor immunity><antitumor vaccine><cancer antigens><cancer cell><cancer immunity><cancer initiation><cancer metastasis><cancer prevention><cancer progression><cancer therapy><cancer type><cancer-directed therapy><cell type><chemo/radiation therapy><chemotherapy and radiotherapy><conventional therapy><conventional treatment><cross reactivity><cytotoxic><develop a vaccine><develop vaccines><development of a vaccine><developmental><efficacy testing><embryonic antigen><embryonic stem cell><exosome><experiment><experimental research><experimental study><experiments><genome mutation><granulocyte macrophage colony stimulating factor><hESC><host response><human ES cell><human ESC><human embryonic stem cell><humanized mice><humanized mouse><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune system response><immunization strategy><immunogen><immunophenotype><immunoresponse><in vivo><infiltration of tumors by immune cells><insight><intercellular communication><intratumoral immune cell><intratumoral immune infiltrate><lung cancer><lung cancer prevention><lung development><lung tumorigenesis><mRNA><malignancy><membrane structure><miRNA><miRNAs><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><novel><oncofetal antigen><oncofetal proteins><oncogenic agent><ontogeny><patient derived xenograft model><prevent><preventing><prophylactic><radiation or chemotherapy><relapse risk><resistant><response><screening><screenings><self-renew><self-renewal><stem cell biomarkers><stem cell derived exosomes><stem cell exosomes><stem cell markers><stem cell of embryonic origin><stem cells><trait><transgenic><translational opportunities><translational potential><tumor><tumor cell metastasis><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><tumor progression><tumor-specific antigen><tumorigenesis in the lung><vaccination strategy><vaccine development><vaccine efficacy><vaccine for cancer><validations><xeno-transplant><xeno-transplantation>