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Single-Cell Lineage Mapping of Elite CAR-NK Cells

   School of Biomedical Sciences

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  Dr R Sugimura  Applications accepted all year round  Funded PhD Project (Students Worldwide)

About the Project

The advance of chimeric antigen receptor (CAR) technology has been a breakthrough in cancer immunotherapy. However, it is not clear in which subpopulation of immune cells the endowment of CAR will be most effective in treating cancer. For example, a certain subpopulation of memory T-cells will be more effective than other T-cells if used as a source of CAR-T cells. Natural killer (NK) cells have been a preferable source of CAR immunotherapy, with less adverse effect than CAR-T cells. CAR-NK cells have been still at the preliminary stage in clinics. We still do not understand in which subpopulation of NK-cells the endowment of CAR will be most effective in treating cancer. We, The Blood Engineering Lab (BEL) at the University of Hong Kong, will employ single-cell lineage mapping and define the ‘elite’ NK-CAR cells that will be most effective in treating cancer. We will establish and utilize a molecular barcoding system. The barcodes will be generated based on CRISPR-Cas9 indel and embedded in the genome. The transcription of each barcode will be captured by single-cell RNA-sequencing as well as the transcriptome. The identification of both the lineage and cell types at a single-cell level will define the ancestor-descendant of the cells of interest. We will apply this approach in CAR-NK generated from human pluripotent stem cells. Upon injection of barcoded CAR-NK cells in tumour-bearing mice, we will define the subpopulation of CAR-NK cells that maintain their functionality, unlike other exhausted populations. We will then define genes differentially expressed in the ‘elite’ subpopulation vs. others. We will identify the role of candidates genes by the CRISPR-based perturb-sequencing approach. The validated genes will be induced in the ancestor population identified from barcodes and will reproduce the generation of elite NK-CAR cells. A Ph.D. student will be involved in the analysis of molecular barcoding, generation of NK-CAR cells, and CRISPR-based perturb-sequencing. S/he is expected to learn the skills in CRISPR-Cas9, single-cell RNA-sequencing analysis, CAR technology, stem cells culture, and differentiation of NK cells.


Dr Rio Sugimura received his M.D. from Osaka University, Japan, in 2008, and his Ph.D. in Stem Cells and Regeneration from the Stowers Institute for Medical Research, USA, in 2012. He has been trained at world-leading institutes, including Harvard Medical School and Kyoto University. He is an Assistant Professor in the School of Biomedical Sciences, The University of Hong Kong. Dr Sugimura is a full faculty member of the Stem Cells & Regeneration Section in F1000Prime, a member of American Association of Immunologists (AAI), American Society of Hematology (ASH), Biomedical Engineering Society (BMES), Association for Cancer Immunotherapy (CIMT), Federation of American Societies for Experimental Biology (FASEB), International Society of Experimental Hematology (ISEH), International Union of Immunological Societies (IUIS), the North American Vascular Biology Organization (NAVBO), Society for Immunotherapy of Cancer (SITC), and a co-founder of the medical branch of Kagakusha-Net. Dr. Sugimura is a recipient of the ASH Scholar Award, March of Dimes, Early Career Grant from Japanese Ministry, Genius Award from Young Hematologist Meeting in Japan, Takeda Science Foundation, iPS Academia Japan Foundation, SMRF Fellowship, Kanehara Memorial Foundation, and Uehara Memorial Foundation. Dr. Sugimura mastered grantsmanship at the Cold Spring Harbor Laboratory Scientific Writing Retreat 2019. Dr Sugimura supervised one postdoctoral fellow, one medical student, three Ph.D. students, two master students, and three undergraduate students.
1. Sugimura, R., Jha, D., Han, A., Soria-Valles, C., da Rocha, E., Lu, Y., Goettel, J., Serrao, E., Rowe, R., Malleshaiah, M., Wong, I., Sousa, P., Zhu, T., Ditadi, A., Keller, G., Engelman, A., Snapper, S., Doulatov, S., Daley, G. (2017) Hematopoietic Stem and Progenitor Cells from Human Pluripotent Stem Cells. Nature. 545, 432-438.
2. Venkatraman, A., He, X.C., Thorvaldsen, J., Sugimura, R., Perry, P., Tao, F., Zhao, M., Christenson, M., Sanchez, R., Yu, J., Peng, L., Haug, J., Paulson, A., Li, H., Zhong, X., Clemens, T., Bartlomei, M., Li, L. (2013). Maternal-imprinting at H19-Igf2 locus maintains adult hematopoietic stem cell quiescence. Nature. 500, 345-349.
3. Sugimura, R., He, X.C., Venkatraman, A., Arai, F., Box, A., Semerad, C., Haug, J., Peng, L., Zhong, X., Suda, T., Li, L. (2012). Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell. 150, 351-365.
4. Perry, J.M., He, X.C., Sugimura, R., Grindley, J.C., Haug, J.S., Ding, S., and Li, L. (2011). Cooperation between both Wnt/{beta}-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion. Genes & development. 25, 1928-1942.
Dr Sugimura is an accomplished scientist, recognized for his outstanding contributions to the field of haematology and stem cell biology. He is interested in using single-cell barcoding technology to delineate single-cell lineage maps of blood/immune cells in human organoids and exploring druggable targets of anti-cancer immunity. His major contribution includes identification of the crucial cellular metabolisms that regulate blood stem cells (Sugimura, 2012. Cell), and exploitation of the genetic program to specify blood stem cells from human pluripotent stem cells (Sugimura, 2017. Nature). Before joining HKU, Dr Sugimura established platforms of human immune cell-generating organoids (Ohta & Sugimura, 2019. JoVE) and organ-on-a-chip (Sugimura, 2020. Biomed. Microdevices). He has published more than 12 peer-reviewed articles in leading journals, such as Nature, Cell, and Genes & Development, received 1,202 citations (Google Scholar).
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