Type 17 CD8+ T cells display enhanced antitumor immunity

Abstract

IntroductionInfusion of tumor-reactive T cells is emerging as an effective treatment for Epstein-Barr virus-associated malignancies and for melanoma. 1-3 T cells with reactivity against tumor antigens can be generated through T-cell receptor (TCR) gene engineering, 4 expanded in vitro, and administered to patients. 5 This approach permits not only targeting of any antigen for which a TCR can be isolated but also selection and induction of T-cell subsets with optimal therapeutic potential. Identification of these subsets is a critical challenge in the advance of cancer immunotherapy. 6,7 Th17-lineage CD4 ϩ T cells, which express the transcription factor ROR-␥t and produce the proinflammatory cytokine interleukin-17 (IL-17), demonstrate enhanced antitumor immunity. 8,9 IL-17-producing CD8 ϩ T cells have been identified in mice and in humans, 10-13 and they can be generated through in vitro priming with Th17-polarizing cytokines. 14 However, a role for these cells in antitumor immunity has not been described. CD4 ϩ T cells can differentiate into lineages with diverse effector functions. In contrast, CD8 ϩ T cells, through the redundant expression of Eomes and T-bet, are fated to develop into cytolytic effector cells that produce IFN-␥ and express granzyme B and perforin. 11,15 It is not known if induction of IL-17 production in this cytolytic lineage would enhance its ability to mediate tumor destruction. Interestingly, the improved antitumor immunity observed with Th17 cells appears to be IL-17-independent, suggesting that it is not IL-17 secretion per se, but rather another characteristic conferred by Th17-polarization, that improves their function. 8 To study tumor therapy with type 17-skewed CD8 ϩ T cells, we used the pmel-1 model of adoptive immunotherapy of B16 melanoma. 16 This model reproduces the clinical challenge of targeting the shared tumor/self-antigen, gp100, in poorly immunogenic, vascularized B16 melanoma tumors. Pmel-1, gp100-specific, TCR-transgenic CD8 ϩ T cells that were primed and expanded before infusion were used to parallel human peripheral blood lymphocytes that are TCR transduced and expanded for clinical therapy. 5 Methods Mice and tumor linesPmel-1/Thy1.1 TCR-transgenic mice have been described previously. 16,17 They were housed in the National Institutes of Health (NIH) Clinical Research Center vivarium and maintained in compliance with the NIH Animal Care and Use Committee. C57BL/6 mice were purchased from The Jackson Laboratory. The B16F10 and MCA205 tumor lines were obtained from the National Cancer Institute (NCI) tumor repository. All animal studies were approved by the NCI Animal Care and Use Committee. In vitro assaysType 17 skewing was accomplished by priming pmel-1/Thy1.1 splenocytes with 1 M hgp100 25-33 in rmIL-6 (5 ng/mL) and recombinant human transforming growth factor-␤ (rhTGF-␤; 10 ng/mL; R&D Systems), and anti-IFN-␥ (10 g/mL; eBioscience). Beginning 2 days after priming, cell cultures were expanded with rhIL-2 (30 IU/mL; Novartis). Control cells were primed and expand...

Dendritic and tumor cell fusions transduced with adenovirus encoding CD40L eradicate B-cell lymphoma and induce a Th17-type response

“…In fact, our data are consistent with recent findings showing that Th17 cells producing IFN-g are capable of mediating regression of established tumors in some murine models. 44,46,47 Collectively, our data suggest that, in our model, Th17-polarized cells mainly mediated tumor 45 Further studies with a selective depletion of effector cells will help to elucidate the exact role that these cells have in the observed antitumoral effect. In summary, we have shown that hybrids of tumor cells and DCs transduced with CD40L induce systemic antitumor immunity, which, in contrast to untransduced fused cells, can eradicate established tumors.…”

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

“…To our knowledge, this is the first report demonstrating tumor-promoting properties of gd T cells, which is quite different from the generally reported tumor-inhibiting properties of skin-resident Vg5 1 gd T cells. Recent studies have shown that tumor antigen-specific Th17 or Tc17 cells, which were induced in vitro, were converted into IFN-g-producing cells after transfer into tumor-bearing mice and subsequently eradicated tumor cells [45,46]. In contrast, IL-17-producing gd T cells did not produce IFN-g in the tumor microenvironment in parallel with the decrease of their cytotoxic function.…”

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

“…5,6 In addition, strategies that enhance the plasticity of Tc17 cells in tumor-bearing subjects and the development of Tc1-like cytokine patterns have been shown to result in stronger antitumor immunity due to increased cell persistence and cytotoxicity. 20,21 Efforts to inhibit Tc17 cell activity are likely to result in a valuable strategy for treating cancer; 52 indeed, CTLA-4 blockade is well known to augment the antitumor activity of T cells in patients with advanced melanoma. 32 Unwanted IL-17 production by continuous CTLA-4 signaling may be the major contributor to the pathological effects of Tc17 cells, not only in the tumor environment but also in autoimmunity.…”

“…16,17 Tc17 cells have been shown to be tumor-promoting cells, but they can also contribute to tumor rejection. [18][19][20] The first sight controversy about the role of Tc17 cells in tumor biology might occur because Tc17 cells easily convert into Tc1-like cells in a pro-inflammatory environment, which rescues their killing capacity while maintaining some of their Tc17 characteristics, such as cell longevity. 21,22 Indeed, some studies have shown that adoptive transfer of tumor-specific Tc17 cells into tumorbearing mice induces potent antitumor activity in an IFNgdependent manner.…”

“…Furthermore, adoptively transferred Tc17 cells were plastically converted into Tc1-like cells, improving the long-term cure rates in mice. 20,21,23,24 Thus, the factors that determine Tc17 plasticity or stability remain of major interest to improve antitumor therapies.…”