Abstract
Memory CD8+ T cells have long been considered a promising population for adoptive cell therapy (ACT) due to their long-term persistence and robust re-stimulatory response. NIH3T3 is an immortalized mouse embryonic fibroblast cell line. We report that NIH3T3-conditioned medium (CM) can augment effector functions of CTLs following antigen priming and confer phenotypic and transcriptional properties of central memory cells. After NIH3T3-CM-educated CTLs were infused into naïve mice, they predominantly developed to central memory cells. A large number of NIH3T3-CM-educated CTLs with high functionality persisted and infiltrated to tumor mass. In addition, NIH3T3-CM inhibited CTLs expression of PD-1 in vitro and repressed their high expression of PD-1 in tumor microenvironment after adoptive transfer. Consequently, established tumor models showed that infusion of NIH3T3-CM-educated CTLs dramatically improved CTL mediated-antitumor immunity. Furthermore, NIH3T3-CM also promoted human CD8+ T cells differentiation into memory cells. These results suggest that NIH3T3-CM-programmed CTLs are good candidates for adoptive transfer in tumor therapy.
Highlights
Adoptive cell therapy (ACT) using autologous tumor reactive T cells has emerged as a potentially curative therapy for cancers [1,2,3]
One prominent notion that has been accepted is that once naïve CD8+T cells are primed, the majority of effector Cytotoxic T lymphocytes (CTLs) will die via differentiation into short-lived effector cells (SLECs) while only a small subset will differentiate into memory precursor effector cells (MPECs) destined to become long-lived memory cells [10,11,12,13]
The level of IFN-γ peaked at 24 h and declined thereafter. It seemed that NIH3T3-conditioned medium (CM) could expedite kinetic IFN-γ production of CTLs compared to that of medium alone-cultured CTLs which peaked at 72 h (Figure 1A, top panel)
Summary
Adoptive cell therapy (ACT) using autologous tumor reactive T cells has emerged as a potentially curative therapy for cancers [1,2,3]. One prominent notion that has been accepted is that once naïve CD8+T cells are primed, the majority of effector CTLs will die via differentiation into short-lived effector cells (SLECs) while only a small subset will differentiate into memory precursor effector cells (MPECs) destined to become long-lived memory cells [10,11,12,13]. In this regard, exploring a proper culture condition to direct the differentiation of tumor-specific CD8+ T cells to MPECs may be a promising approach to develop a curative antitumor therapy upon adoptive transfer
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