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 _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

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

Metrics: PDF 1463 views  |   HTML 1529 views  |   ?  


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


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 8197