CD8+ iT cell, a budding star for cancer immunotherapy
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Adoptive cellular therapy
Chimeric antigen receptor expressing T cell
T cell-induced pluripotent stem cell
Induced hematopoietic stem cells
T cell receptor
Early T cell lineage progenitor-like cells
Notch receptor ligand Delta-like 1/4
The fate of hematopoietic cell can be modified or totally overset by genetic engineering technique. Attempts to convert B into T cells by silencing “master genes” of the B cell lineage have had limited success (Cobaleda et al. 2007; Ungerback et al. 2015). Recently, a report showed that expression of hematopoietic stem cell-specific transcription factor Homeobox B5 (Hoxb5) in mouse B cell progenitors successfully reprogramed those cells into functional T cells in vivo. This de novo approach is potentially capable to generate T cells for adoptive T cell therapy (ACT) in future. Here, we summarized a brief commentary on the application prospect of this induced functional T cell (iT) generation strategy by this reprogramming approach.
Chimeric antigen receptor T cells (CAR-T) and T cell receptor T cells (TCR-T) are promising forms of immunotherapy against leukemia and solid tumors (Im and Pavletic 2017; Lin et al. 2017; Kasakovski et al. 2018). However, conventional CAR-T and TCR-T cell products are mainly derived from the autologous peripheral blood of patients, whose T cells occasionally showed functional exhaustion and senescence and reduced response to activation, which were correlated with patient’s age, tumor burden, or microenvironment (Crespo et al. 2013; Vicente et al. 2016; Lin et al. 2017; Kasakovski et al. 2018). In order to overcome difficulties faced in CAR-T and TCR-T production, which were caused by the limited quantity, function impairment, and the terminally differentiated state of autologous T cells from patients, an alternative approach has been attempted in the T cell regenerative filed by generating tumor-targeted T cells from induced pluripotent stem cells (iPSCs), which are reprogrammed from somatic cells, such as peripheral blood cells and even T cells (Loh et al. 2010; Themeli et al. 2013; Vizcardo et al. 2013).
Published studies have shown that pro-B cells are highly plastic for reprogramming (Xie et al. 2004; Cobaleda et al. 2007), and these cells have been successfully converted into T cells by dedifferentiation to uncommitted blood progenitors (Cobaleda et al. 2007; Ungerback et al. 2015). Recently, Wang and colleagues reported that iT cells can be generated by the expression of hematopoietic stem cell (HSC)-specific transcription factor Hoxb5 in pro-pre-B cells in vivo. Surprisingly, Hoxb5 directly reprogrammed B cells into early T cell lineage progenitor-like cells (ETPs) by a trans-differentiation process, since no donor-derived uncommitted hematopoietic progenitor cells were detected in the recipient mice. The induced ETPs in bone marrow can further complete mature T cell development in the thymus microenvironment and finally express polyclonal TCR β chains. The mature T cell derivatives were capable of secreting IL-2, IL-10, IFN-γ, and TNF cytokines in response to monoclonal anti-CD3 and anti-CD28 antibody stimulation and capable of proliferating after allogenic cell stimulation in vitro. Furthermore, in vivo study identified that these iT cells rejected allogenic skin graft and formed adaptive immunological memories (Zhang et al. 2018). Despite the efficiency of lineage conversion being currently low (1%), pro-pre-B cells expressing retro-Hoxb5 failing to generate ETPs were still able to differentiate normally into B cells, which reduces the risk of generating unknown pluripotency cells with tumor potential. It has been considered as a potential risk of iT cells by reprogramming and induction approaches (Loh et al. 2010; Vizcardo et al. 2013). In addition, the shorter lifespan of those iT cells also decreased the tumorigenesis risk compared with those less differentiated cell types. Thus, CD8+ iT cells generated by this single transcription factor reprogramming might be potentially applied to treat lymphocytopenia-related autoimmune deficiency diseases. Particularly, when combined with antitumor-specific TCR gene or CAR-T gene transfer, they could be one possible source of T cell generation for treating metastatic cancer and virus infection, especially for who do not have enough natural tumor- or virus-specific T cells for ACT.
Generating fully functional T cells in vivo by ectopic expression of HSC transcription factor Hoxb5 in pro-pre-B cells holds great promise for treating patients who suffer with T cell immune deficiency diseases in the future. Combined with CAR and tumor antigen-specific TCR gene transfer techniques, they are also promising in cancer immunotherapy; however, a lot of challenges are still facing before arrive at the real clinical transformation.
YQL designed the review and helped to modify the manuscript. LX drafted the manuscript and prepared the figures. ZYJ drafted the manuscript. All authors read and approved the final manuscript.
This study was supported by grants from the National Natural Science Foundation of China (Nos. 91642111, 81770152), the Guangdong Provincial Basic Research Program (No. 2015B020227003), the Guangdong Provincial Applied Science and Technology Research & Development Program (No. 2016B020237006) and the Guangzhou Science and Technology Project (Nos. 201510010211, 201807010004 and 201803040017).
Compliance with ethical standards
The authors declare that they have no competing interests.