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

Ingunn M. Stromnes, Carla Fowler, Chanel C. Casamina, Christina M. Georgopolos, Megan S. McAfee, Thomas M. Schmitt, Xiaoxia Tan, Tae Don Kim, Inpyo Choi, Joseph Blattman, Philip D. Greenberg

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1812-1825
Number of pages14
JournalJournal of Immunology
Volume189
Issue number4
DOIs
StatePublished - Aug 15 2012
Externally publishedYes

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SH2 Domain-Containing Protein Tyrosine Phosphatases
Adoptive Immunotherapy
src Homology Domains
T-Lymphocytes
Neoplasms
Autoantigens
Cell- and Tissue-Based Therapy
Immunotherapy
Small Interfering RNA
Interleukin-2
Leukemia
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

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. / 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; Greenberg, Philip D.

In: Journal of Immunology, Vol. 189, No. 4, 15.08.2012, p. 1812-1825.

Research output: Contribution to journalArticle

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 ; Greenberg, Philip D. / 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. In: Journal of Immunology. 2012 ; Vol. 189, No. 4. pp. 1812-1825.
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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.",
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AU - Fowler, Carla

AU - Casamina, Chanel C.

AU - Georgopolos, Christina M.

AU - McAfee, Megan S.

AU - Schmitt, Thomas M.

AU - Tan, Xiaoxia

AU - Kim, Tae Don

AU - Choi, Inpyo

AU - Blattman, Joseph

AU - Greenberg, Philip D.

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AB - 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.

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