Memoirs of a reincarnated T cell

Abstract

In two studies published in this issue of Cell Stem Cell,Nishimura et al. (2013) and Vizcardo et al. (2013) reprogram mature, antigen-specific cytotoxic T cells into induced pluripotent stem cells (iPSCs). The antigen-specific iPSCs can be redifferentiated into "rejuvenated" proliferative T cells and have broad applications for adoptive immunotherapy.

Figure 1.. Reprogramming an Exhausted Immune System for Treatment of Cancer

(A) Generalized model of T cell differentiation. An immune response is initiated when naive CD8⁺ T cells (T_N) are activated by their cognate antigen to undergo clonal expansion and differentiation into subsets characterized here by a reciprocally graded capacity for self-renewal and cytolytic effector function. Although eradication of tumor ultimately requires robust cytolytic function of terminally differentiated effector (T_EFF) cells, therapeutic efficacy of ACT is improved by transfer of less-differentiated cells because of their ability for self renewal and survival and their ability to generate T_EFF progeny. (B) Rejuvenating T cells with Yamanaka factors. Adoptive T-cell-based immunotherapy (ACT) for cancer involves isolating CD8⁺ lymphocytes from a surgically excised tumor and expanding the cells ex vivo with T cell growth factor IL-2. Lymphocytes are subsequently infused back into the patient to attack the remaining tumor sites. Lymphocytes isolated from the tumor generally have a terminally differentiated effector (T_EFF) or effector memory (T_EM) phenotype, and the IL-2 driven expansion results in further differentiation. There is considerable evidence that transfer of less-differentiated lymphocytes such as stem-cell memory T cells (T_SCM) or central memory T cells (T_CM) results in substantially greater antitumor immunity. Therefore, rejuvenating lymphocytes to a less-differentiated state using induced pluripotent stem cell (iPSC) technology shows great promise in substantially improving the efficacy of ACT. Reprogramming with Yamanaka factors and redifferentiation with Delta-like 1 expressing OP9 (OP9/DLL1) stromal cells rejuvenates lymphocytes and preserves less-differentiated T_SCM and T_CM CD8⁺ T cell subsets that may result in improved eradication of tumor when transferred into cancer patients.