Neoantigen Specific T Cells Derived From T Cell-Derived Induced Pluripotent Stem Cells for the Treatment of Hepatocellular Carcinoma: Potential and Challenges

Abstract

Immunotherapy has become an indispensable part of the comprehensive treatment of hepatocellular carcinoma (HCC). Immunotherapy has proven effective in patients with early HCC, advanced HCC, or HCC recurrence after liver transplantation. Clinically, the most commonly used immunotherapy is immune checkpoint inhibition using monoclonal antibodies, such as CTLA-4 and PD-1. However, it cannot fundamentally solve the problems of a weakened immune system and inactivation of immune cells involved in killing tumor cells. T cells can express tumor antigen-recognizing T cell receptors (TCRs) or chimeric antigen receptors (CARs) on the cell surface through gene editing to improve the specificity and responsiveness of immune cells. According to previous studies, TCR-T cell therapy is significantly better than CAR-T cell therapy in the treatment of solid tumors and is one of the most promising immune cell therapies for solid tumors so far. However, its application in the treatment of HCC is still being researched. Technological advancements in induction and redifferentiation of induced pluripotent stem cells (iPSCs) allow us to use T cells to induce T cell-derived iPSCs (T-iPSCs) and then differentiate them into TCR-T cells. This has allowed a convenient strategy to study HCC models and explore optimal treatment strategies. This review gives an overview of the major advances in the development of protocols to generate neoantigen-specific TCR-T cells from T-iPSCs. We will also discuss their potential and challenges in the treatment of HCC.

Keywords: T cell receptors; T cell-derived induced pluripotent stem cells; T cells; hepatocellular carcinoma; immunotherapy; neoantigen.

Figure 1

The current treatments for liver cancer include hepatectomy, immunotherapy, transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), targeted drug therapy (sorafenib/FOLFOX4), and liver transplantation (UCSF standard). According to the patient’s condition, such as the degree of liver cirrhosis, liver function (child grade), number of tumors, size of tumors, and metastasis, clinicians select the appropriate treatment plan or perform combination therapy.

Figure 2

Mature CD8+ T cells with a new antigen-specific TCR gene can recognize antigen targets and thus attack and kill tumor cells. TCR, T cell receptor; HLA, human leukocyte antigen; MHC, major histocompatibility complex.

Figure 3

Brief history of T cell-derived induced pluripotent stem cells (T-iPSCs). TCR, T Cell Receptor; iPSCs, induced pluripotent stem cells; CTLs, cytotoxic T lymphocytes.

Figure 4

Preparation of new antigen-specific TCR-T cells. First, T cells with new antigen-specific TCR rearrangement gene were isolated from the body. Second, after adding OCT3/4, Sox2, KLF4, and c-MYC, T cells were induced to T-iPSC. Third, in the presence of bone marrow mesenchymal stem cells (C3H10T1/2), vascular endothelial growth factor (VEGF), stem cell factor (SCF), and tyrosine kinase ligand 3 (FLT-3L), T-iPSCs were differentiated into mesodermal CD34+ hematopoietic stem cells (HSCs) and hematopoietic progenitor cells. Cells were transfected to OP9-DL1 FLT-3 and IL-7 culture medium to obtain T cell lineage. Thus, a large number of T cells will be used to recognize and kill tumor cells.