Advancing cell-based immunotherapies using next-generation genetic tools
Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Chen, Sidi
Abstract
We are at a critical juncture in which the application of genome-editing technologies and multi-omic modalities to immunological studies are enabling rapid discovery of novel genes and regulatory pathways that can be modulated to direct both local and systemic immune responses (Bock et al., 2022; Dong et al., 2022; Hasin et al., 2017). At the center of these advancements is CRISPR, a technology adapted from a family of bacterial endonucleases that can be programmed with CRISPR RNAs (crRNAs) bearing spacer sequences that are complementary to nearly any region of the genome (Cong et al., 2013; Jinek et al., 2012; Mali et al., 2013; Shivram et al., 2021). Here, I first discuss how CRISPR and multi-omic technologies have been utilized to study the function of different immune cells in cancer (Dong et al., 2022). Next, I applied these principles to identify negative regulators of antitumor CD8 T cell responses in mouse models of breast cancer and glioblastoma using CRISPR-Cas9 (Dong et al., 2019; Ye et al., 2019). In my third study, I generated the novel transgenic CRISPR-LbCas12a mouse that enables simultaneous multiplexed gene editing in primary murine immune cells. Finally, I developed a human CD4 CAR-T cell platform using CRISPR-LbCas12a ribonucleoproteins to transcriptionally rewire human CD4 T cells towards various CD4 T helper cell lineages. Collectively, I hope to convey how CRISPR technologies can be employed to further our understanding of immunological processes and how it can be implemented for the development of immunotherapies.
Recommended Citation
Dong, Matthew Bo, "Advancing cell-based immunotherapies using next-generation genetic tools" (2022). Yale Graduate School of Arts and Sciences Dissertations. 712.
https://elischolar.library.yale.edu/gsas_dissertations/712
