1. Abrogation of Src Homology Region 2 Domain-Containing Phosphatase 1 in Tumor-Specific T Cells Improves Efficacy of Adoptive Immunotherapy by Enhancing the Effector Function and Accumulation of Short-Lived Effector T Cells In Vivo.
- Author
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Stromnes, Ingunn M., Fowler, Carla, Casamina, Chanel C., Georgopolos, Christina M., McAfee, Megan S., Schmitt, Thomas M., Tan, Xiaoxia, Kim, Tae-Don, Choi, Inpyo, Blattman, Joseph N., and Greenberg, Philip D.
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IMMUNOPATHOLOGY , *IMMUNOTHERAPY , *HOMOLOGY (Biochemistry) , *PHOSPHATASES , *T cells , *PATHOGENIC microorganisms , *CD8 antigen , *LABORATORY mice - Abstract
T cell expression of inhibitory proteins can be a critical component for the regulation of immunopathology owing to self-reactivity or potentially exuberant responses to pathogens, but it may also limit T cell responses to some malignancies, particularly if the tumor Ag being targeted is a self-protein. We found that the abrogation of Src homology region 2 domain-containing phosphatase-1 (SHP-1) in tumor-reactive CD8+ T cells improves the therapeutic outcome of adoptive immunotherapy in a mouse model of disseminated leukemia, with benefit observed in therapy employing transfer of CD8+ T cells alone or in the context of also providing supplemental IL-2. SHP-1-/- and SHP-1+/+ effector T cells were expanded in vitro for immunotherapy. Following transfer in vivo, the SHP-1-/- effector T cells exhibited enhanced short-term accumulation, followed by greater contraction, and they ultimately formed similar numbers of long-lived, functional memory cells. The increased therapeutic effectiveness of SHP-1-/- effector cells was also observed in recipients that expressed the tumor Ag as a self-antigen in the liver, without evidence of inducing autoimmune toxicity. SHP-1-/- effector CD8+ T cells expressed higher levels of eomesodermin, which correlated with enhanced lysis of tumor cells. Furthermore, reduction of SHP-1 expression in tumor-reactive effector T cells by retroviral transduction with vectors that express SHP-1-specific small interfering RNA, a translatable strategy, also exhibited enhanced antitumor activity in vivo. These studies suggest that abrogating SHP-1 in effector T cells may improve the efficacy of tumor elimination by T cell therapy without affecting the ability of the effector cells to persist and provide a long-term response. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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