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

• Published in: The Journal of immunology (1950) 2012-08, Vol.189 (4), p.1812-1825
• Main Authors: 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, Greenberg, Philip D
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - immunology; Disease Models, Animal; Immunotherapy, Adoptive - methods; Leukemia - immunology; Leukemia - therapy; Mice; Mice, Knockout; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - immunology; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes - immunology; T-Lymphocytes - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200552

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.