T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy

Patrick L. Raber, Rosa A. Sierra, Paul T. Thevenot, Zhang Shuzhong, Dorota D. Wyczechowska, Takumi Kumai, Esteban Celis, Paulo C. Rodriguez

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ T cells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/ mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of better strategies to increase ACT responses in cancer.

Original languageEnglish (US)
Pages (from-to)17565-17578
Number of pages14
JournalOncotarget
Volume7
Issue number14
DOIs
StatePublished - Jan 1 2016

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Immunotherapy
T-Lymphocytes
Neoplasms
Sirolimus
Myeloid-Derived Suppressor Cells
Cell Differentiation
Tuberous Sclerosis
T-Cell Antigen Receptor
Population
Interleukin-2
Cell Proliferation

Keywords

  • Adoptive T cell transfer immunotherapy (ACT)
  • Central memory T cells (T)
  • Immune response
  • Immunity
  • Immunology and Microbiology Section
  • Mammalian target of rapamycin (mTOR)
  • Myeloid-derived suppressor cells (MDSC)
  • Stem cell memory T cells (T)

ASJC Scopus subject areas

  • Oncology

Cite this

Raber, P. L., Sierra, R. A., Thevenot, P. T., Shuzhong, Z., Wyczechowska, D. D., Kumai, T., ... Rodriguez, P. C. (2016). T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy. Oncotarget, 7(14), 17565-17578. https://doi.org/10.18632/oncotarget.8197

T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy. / Raber, Patrick L.; Sierra, Rosa A.; Thevenot, Paul T.; Shuzhong, Zhang; Wyczechowska, Dorota D.; Kumai, Takumi; Celis, Esteban; Rodriguez, Paulo C.

In: Oncotarget, Vol. 7, No. 14, 01.01.2016, p. 17565-17578.

Research output: Contribution to journalArticle

Raber, PL, Sierra, RA, Thevenot, PT, Shuzhong, Z, Wyczechowska, DD, Kumai, T, Celis, E & Rodriguez, PC 2016, 'T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy', Oncotarget, vol. 7, no. 14, pp. 17565-17578. https://doi.org/10.18632/oncotarget.8197
Raber PL, Sierra RA, Thevenot PT, Shuzhong Z, Wyczechowska DD, Kumai T et al. T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy. Oncotarget. 2016 Jan 1;7(14):17565-17578. https://doi.org/10.18632/oncotarget.8197
Raber, Patrick L. ; Sierra, Rosa A. ; Thevenot, Paul T. ; Shuzhong, Zhang ; Wyczechowska, Dorota D. ; Kumai, Takumi ; Celis, Esteban ; Rodriguez, Paulo C. / T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy. In: Oncotarget. 2016 ; Vol. 7, No. 14. pp. 17565-17578.
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abstract = "The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ T cells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/ mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of better strategies to increase ACT responses in cancer.",
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