Generation and clinical potential of functional T lymphocytes from gene-edited pluripotent stem cells

Abstract

Engineered T cells have been shown to be highly effective in cancer immunotherapy, although T cell exhaustion presents a challenge for their long-term function. Additional T-cell sources must be exploited to broaden the application of engineered T cells for immune defense and reconstitution. Unlimited sources of pluripotent stem cells (PSCs) have provided a potential opportunity to generate precise-engineered therapeutic induced T (iT) cells. Single-cell transcriptome analysis of PSC-derived induced hematopoietic stem and progenitor cells (iHSPC)/iT identified the developmental pathways and possibilities of generating functional T cell from PSCs. To date, the PSC-to-iT platforms encounter several problems, including low efficiency of conventional T subset specification, limited functional potential, and restrictions on large-scale application, because of the absence of a thymus-like organized microenvironment. The updated PSC-to-iT platforms, such as the three-dimensional (3D) artificial thymic organoid (ATO) co-culture system and Runx1/Hoxa9-enforced iT lymphopoiesis, provide fresh perspectives for coordinating culture conditions and transcription factors, which may greatly improve the efficiency of T-cell generation greatly. In addition, the improved PSC-to-iT platform coordinating gene editing technologies will provide various functional engineered unconventional or conventional T cells. Furthermore, the clinical applications of PSC-derived immune cells are accelerating from bench to bedside.

Advancements in γδT cell engineering: paving the way for enhanced cancer immunotherapy

“…In addition to γδT cells derived from donors, these cells can also be generated from iPSCs ( 88 , 89 ). Two companies, Century Therapeutics and CytoMed Therapeutics, have developed platforms that enrich γδT cells from healthy donor leukapheresis and then reprogram them into T cell-derived iPSCs (TiPSCs).…”

Personalized cancer avatars for patients with thymic malignancies: A pilot study with circulating tumor cell‐derived organoids

“…For example, drug sensitivity towards regorafenib of organoids from surgical biopsy of metastatic colon cancer tissues have been shown to predict the clinical treatment response to regorafenib 5 . Such technologies have been applied in thymus biology research, including studies of T cell development with artificial thymic organoids and therapeutic T cell engineering 8–10 . Moreover, patient‐derived thymic tumor tissue has been analyzed in a similar approach to uncover the novel role of WNT4 in thymic epithelial carcinogenesis 11 .…”

Targeted single‐cell RNA sequencing analysis reveals metabolic reprogramming and the ferroptosis‐resistant state in hematologic malignancies

“…11 Single-cell sequencing technologies offer valuable means for acquiring diverse cellular states and mutation phenotypes. [12][13][14][15][16][17] Several metabolic studies have relied on tumor cell lines 18 ; however, this approach may undermine their clinical relevance owing to considerable disparities between in vivo and in vitro conditions.…”

“…In contrast to bulk RNA‐seq data, scRNA‐seq data offer a significant advantage for reconstructing the clonal architecture and phylogenetic patterns 11 . Single‐cell sequencing technologies offer valuable means for acquiring diverse cellular states and mutation phenotypes 12–17 . Several metabolic studies have relied on tumor cell lines 18 ; however, this approach may undermine their clinical relevance owing to considerable disparities between in vivo and in vitro conditions.…”