Abrogation of SHP-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

摘要

T cell expression of inhibitory proteins can be a critical component for the regulation of immunopathology due to self-reactivity or potentially exuberant responses to pathogens, but may also limit T cell responses to some malignancies, particularly if the tumor antigen being targeted is a self-protein. We found that the abrogation of 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 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 antigen 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 siRNA, a translatable strategy, also exhibited enhanced anti-tumor 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 impacting the ability of the effector cells to persist and provide a long-term response.