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T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy
- Source :
- Oncotarget
- Publication Year :
- 2016
- Publisher :
- Impact Journals LLC, 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+ 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.
- Subjects :
- 0301 basic medicine
Thymoma
T cell
Cellular differentiation
T-Lymphocytes
Cell Communication
Lymphocyte Activation
Immunotherapy, Adoptive
03 medical and health sciences
Interleukin 21
Carcinoma, Lewis Lung
Mice
adoptive T cell transfer immunotherapy (ACT)
Cell Line, Tumor
medicine
Cytotoxic T cell
Animals
Myeloid Cells
IL-2 receptor
Immune response
central memory T cells (TCM)
business.industry
mammalian target of rapamycin (mTOR)
Research Paper: Immunology
Immunity
CD28
Cell Differentiation
Thymus Neoplasms
3. Good health
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Oncology
T cell differentiation
Immunology
Cancer research
myeloid-derived suppressor cells (MDSC)
Immunology and Microbiology Section
Female
business
stem cell memory T cells (TSCM)
CD8
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 7
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....314eb6dfe19888c93916ea179224b189