Oncotarget

Research Papers: Immunology:

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 and Paulo C. Rodriguez _

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Oncotarget. 2016; 7:17565-17578. https://doi.org/10.18632/oncotarget.8197

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Abstract

Patrick L. Raber1, Rosa A. Sierra2, Paul T. Thevenot3, Zhang Shuzhong2, Dorota D. Wyczechowska4, Takumi Kumai2, Esteban Celis2 and Paulo C. Rodriguez2

1 Adaptive Biotechnologies, Seattle, WA, USA

2 Georgia Regents University Cancer Center, Augusta, GA, USA

3 Institute of Translational Research, Ochsner Medical Center, New Orleans, LA, USA

4 Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA

Correspondence to:

Paulo C. Rodriguez, email:

Keywords: adoptive T cell transfer immunotherapy (ACT), myeloid-derived suppressor cells (MDSC), mammalian target of rapamycin (mTOR), central memory T cells (TCM), stem cell memory T cells (TSCM), Immunology and Microbiology Section, Immune response, Immunity

Received: October 20, 2015 Accepted: March 14, 2016 Published: March 19, 2016

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+ Tcells 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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