Adoptive Transfer of Tc1 or Tc17 Cells Elicits Antitumor Immunity against Established Melanoma through Distinct Mechanisms

Abstract

Adoptive cell transfer (ACT) of ex vivo activated autologous tumor-reactive T cells is currently one of the most promising approaches for cancer immunotherapy. Recent studies provided some evidence that Th17/Tc17 cells may exhibit potent anti-tumor activity, but the specific mechanisms have not been completely defined. In the present study, we used a murine melanoma lung-metastasis model and tested the therapeutic effects of gp100-specific polarized Tc1 or Tc17 cells combined with autologous BMT after total TBI. BMT combined with ACT of anti-tumor (gp100-specific) Tc17 cells significantly suppressed the growth of established melanoma, whereas Tc1 cells induced long-term tumor regression. After ACT, Tc1 cells maintained their phenotype to produce IFNγ but not IL-17. However, although Tc17 cells largely preserved their ability to produce IL-17, a subset secreted IFNγ or both IFNγ and IL-17, indicating the plasticity of Tc17 cells in vivo. Furthermore, after ACT the Tc17 cells had a long-lived effector T cell phenotype (CD127hi/KLRG-1low) as compared to Tc1 cells. Mechanistically, Tc1 cells mediated anti-tumor immunity primarily through the direct effect of IFNγ on tumor cells. In contrast, despite the fact that some Tc17 cells also secreted IFNγ, Tc17-mediated anti-tumor immunity was independent of the direct effects of IFNγ on the tumor. Nevertheless, IFNγ played a critical role by creating a microenvironment that promoted Tc17-mediated anti-tumor activity. Taken together, these studies demonstrate that both Tc1 and Tc17 cells can mediate effective anti-tumor immunity through distinct effector mechanisms, but Tc1 cells are superior to Tc17 cells in mediating tumor regression.

Heterogeneity in the Differentiation and Function of CD8+ T Cells

“…The cytokine IL-12 has been shown to promote the switch of Tc17 toward Tc1 via epigenetic suppression of Socs3, which on the one hand promotes Tc17 generation (Satoh et al 2012;Yu et al 2013) and on the other dampens Tc1 effector development (Cui et al 2011). Interestingly, in allergic airway disease IFN-c-deficient CD8…”

“…Likewise, Tc17 cells maintain IL-17 production but start to produce IFN-c in EAE (Huber et al 2013), in a diabetes model (Saxena et al 2012), in tumor models (Hinrichs et al 2009;Yu et al 2013), during GvHD of mice (Beres et al 2012) and upon viral infection of mice (Yen et al 2009). The cytokine IL-12 has been shown to promote the switch of Tc17 toward Tc1 via epigenetic suppression of Socs3, which on the one hand promotes Tc17 generation (Satoh et al 2012;Yu et al 2013) and on the other dampens Tc1 effector development (Cui et al 2011).…”

Tumor-specific IL-9–producing CD8+Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers

“…In addition, naïve CD8 + T cells can be differentiated into Tc17 cells in Th17 polarizing conditions (8). The effect of Tc17-mediated antitumor responses remains controversial with one group describing enhanced antitumor immunity displayed by Tc17 (8) and two more recent studies demonstrating that Tc1 cells are superior to Tc17 cells in mediating tumor regression after transfer (11,12). However, IL-17 and IL-17-producing T cells are tumor-promoting factors and can mediate IL-6-induced Stat3 activation to generate protumorigenic environment (13), which may limit the application of Tc17 for adoptive therapy.…”

Cyclosporine A Inhibits the T-bet–Dependent Antitumor Response of CD8+ T Cells

“…In this context, the quantification and phenotypic characterization of tumor-infiltrating T cells by immunohistochemistry could provide further insights into this issue. Apart from that, Tc17 cells control tumor growth in a mechanistically different way than Tc1 T cells, the antitumor effects of which are largely dependent on IFN-g (28) that is produced in a T-bet-dependent manner (29).…”