Friday, April 19, 2024
4/19/2024
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.
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