Developing synthetic yeast-based cell-cell communication tools for immune cell activation and manipulation

Marcus Deichmann

Research output: Book/ReportPh.D. thesis

26 Downloads (Pure)

Abstract

Synthetic biology continues to revolutionize the landscape of cellular engineering, paving the way for the advancement of programmable cells that can solve humanity's biological challenges. Novel genetic engineering strategies enable the customization of artificial sense-response functions in cells, which use sophisticated gene circuits to achieve precise control in both microbial and human cell systems. Specifically, the engineering of human immune cells holds significant potential for treating a range of diseases, as demonstrated by chimeric antigen receptor (CAR) T cell immunotherapy for hematological cancers, such as leukemia and lymphoma. However, the efficacy of these cellular therapies is challenged by an incomplete understanding of the complex interactions between the immune system and cancers. In this thesis, the yeast Saccharomyces cerevisiae is engineered to facilitate artificial interspecies cell-to-cell communication with human immune cells to address this challenge by enabling the modulation and characterization of immune cell phenotypes. Initially, the engineerability of yeast behavior is explored by linking natural yeast mating with human neurotransmitter signaling and then leveraged to establish a whole-cell synthetic biology tool, named the Synthetic Cellular Advanced Signal Adapter (SCASA) system. The SCASA yeast cells enable the controlled simulation of human cancer cells and allow for the assessment of responses from immunotherapeutic CAR T cells. Hence, these engineered yeast cells are here employed to characterize FDA-approved CAR T cell designs, validate the functionality of a novel donor-derived CAR T cell product, and map uncharacterized intracellular CAR signaling dynamics through phosphoproteomic analyses. This thesis explores the challenges and opportunities in T-cell engineering and yeast synthetic biology, offering insights and suggested future directions for advancing these fields collectively.
Original languageEnglish
Number of pages248
Publication statusPublished - 2024

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