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.
Highlights
Adoptive T cell-based immunotherapy (ACT) to eliminate tumor cells, or to prevent their recurrence, represents an emerging treatment for patients with various malignancies [1, 2]
We monitored the expression of the differentiation markers, CD44 and CD62L, in SIINFEKL-activated CD8+ T cells from OT-1 mice co-cultured with tumor-Myeloid-derived suppressor cells (MDSC) or non-suppressive immature myeloid cells
An elevated percentage of undifferentiated CD44low CD62L+ CD8+ T cells was found in SIINFEKL-primed OT-1 cells treated with MDSC, compared to those exposed to immature myeloid cells (iMC), which progressed mainly into CD44high CD62L+ TCM cells (Figure 1A)
Summary
Adoptive T cell-based immunotherapy (ACT) to eliminate tumor cells, or to prevent their recurrence, represents an emerging treatment for patients with various malignancies [1, 2]. While MDSC have been closely linked to the inhibition of T cell migration, proliferation, and expression of effector molecules [9], it remains unclear the impact of MDSC on the differentiation of CD8+ T cells into effector populations and on T cell efficacy after ACT. Protective anti-tumor T cell immunity, and the success of ACT, requires differentiation of CD8+ T www.impactjournals.com/oncotarget cells into cytolytic and cytokine-producing effector cells [10]. Acquisition of full effector function before ACT impairs the anti-tumor effect of CD8+ T cells [12]. Transfer of activated undifferentiated CD44low CD62L+ CD8+ T cells (referred as stem cell memory T cells (TSCM)) into tumor-bearing mice resulted in higher anti-tumor responses, compared to those found in mice receiving TEM cells [13]. Inhibition of CD8+ T cell differentiation increased their efficacy after ACT
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