title: T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy.
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.
authors.affiliation: Adaptive Biotechnologies, Seattle, WA, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Raber
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA, USA.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Sierra
authors.affiliation: Institute of Translational Research, Ochsner Medical Center, New Orleans, LA, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Thevenot
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA, USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Shuzhong
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Dorota D
authors.initials: DD
authors.lastname: Wyczechowska
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA, USA.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kumai
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA, USA.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013945:Thymoma / Q000276:immunology / Q000628:therapy; D013953:Thymus Neoplasms / Q000276:immunology / Q000628:therapy
keywords: Immune response; Immunity; Immunology and Microbiology Section; adoptive T cell transfer immunotherapy (ACT); central memory T cells (TCM); mammalian target of rapamycin (mTOR); myeloid-derived suppressor cells (MDSC); stem cell memory T cells (TSCM)