Cutting Edge: IFN-γ Enables APC to Promote Memory Th17 and Abate Th1 Cell Development

Kryczek, Ilona; Wei, Shuang; Gong, Wenrong; Shu, Xiaogong; Szeliga, Wojciech; Vatan, Linhua; Chen, Lieping; Wang, Guobin; Zou, Weiping

doi:10.4049/jimmunol.181.9.5842

Cited by 80 publications

(82 citation statements)

References 31 publications

(52 reference statements)

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“…Macrophages outnumbered myeloid DCs in ovarian cancer 19,21 (supplemental Figure 3) and were superior to inducing Th17 cells than myeloid DCs (supplemental Figure 4, Figure 3B). 29 Our subsequent studies focused on tumor-associated macrophages.…”

Section: Induction and Suppression Of Th17 Cell Development In The Tumentioning

confidence: 99%

Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments

Kryczek¹,

Banerjee

Cheng

et al. 2009

Blood

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IntroductionAdaptive immunity plays a crucial role in tumor immunosurveillance. [1][2][3] It has been shown that tumor-infiltrating effector T cells are associated with improved prognoses in multiple human cancers, 4-6 whereas tumor-infiltrating regulatory T (Treg) cells are negatively associated with patient outcome. 6,7 Th17 cells are newly identified effector CD4 ϩ T cells. Th17 cells and interleukin-17 (IL-17) play an active role in inflammation and autoimmune diseases. [8][9][10][11][12][13][14][15] Th17 cells are found in both mouse and human tumors. 16,17 However, the biologic role of Th17 cells is poorly understood in the tumor microenvironment. In this report, we examined the phenotype, cytokine profile, generation, functional relevance, and immunologic and clinical predictive values of Th17 cells in 201 patients with ovarian cancers. We provide novel insight into the nature of Th17 cells in the tumor microenvironment in patients with cancer. This information may be useful for designing more effective cancer immunotherapies. Methods Human subjectsWe studied previously untreated patients with 201 ovarian carcinomas. Survival data were available for 85 patients (supplemental Table 1, available on the Blood website; see the Supplemental Materials link at the top of the online article). Patients gave written, informed consent in accordance with the Declaration of Helsinki. The study was approved by the University of Michigan Institutional Review Board. Cells and tissuesCells and tissues were obtained from ascites, blood, lymph nodes, and tumors as we described. 16,18,19 Immune cells, including monocytes, macrophages, myeloid dendritic cells, plasmacytoid dendritic cells, and T-cell subsets, were enriched using paramagnetic beads (StemCell Technologies) and sorted with FACSAria (Becton Dickinson) as we described. 16,18,19 Cell purity was more than 98% as confirmed by flow cytometry (LSR II; Becton Dickinson). FACSFor cytokine detection, the cells were stimulated with phorbol myristate acetate (50 ng/mL; Sigma-Aldrich), ionomycin (1 M; Sigma-Aldrich) for 4 hours before staining. Cells were first stained extracellularly with specific antibodies against human CD3, CD4, CD8, CD11b, CD11c, CD14, CD15, CD16, CD19, CD25, CD39, CD45, CD45RO, CD49a, CD49c, CD49d, CD49e, CD56, CD123, CD161, PD-1, CCR4, CCR6, CCR7, CXCR4, HLA-DR, and annexin V (BD Biosciences), CCR2, CXCR3, and CCR5 (R&D Systems), EpCam (StemCell Technologies), then were fixed and permeabilized with Perm/Fix solution (eBioscience), and finally were stained intracellularly with anti-IL-2, anti-IL-10, anti-IL-17, anti-tumor necrosis factor-␣, anti-interferon-␥ (IFN-␥), anti-Granzyme A, anti-Ki-67, and anti-FOXP3 (all from BD Biosciences, except anti-IL-17, eBioscience). Samples were acquired on a LSR II (BD Biosciences), and data were analyzed with DIVA software (BD Biosciences). Th17 induction and suppressionFresh peripheral blood and tumor-associated CD14 ϩ macrophages were sorted 19 and cocultured with T cells as indicated for 3 to 5 days in the An In...

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Section: Induction and Suppression Of Th17 Cell Development In The Tumentioning

confidence: 99%

Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments

Kryczek¹,

Banerjee

Cheng

et al. 2009

Blood

Self Cite

690

682

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“…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][11][12][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.…”

Section: Introductionmentioning

confidence: 99%

Type 17 CD8+ T cells display enhanced antitumor immunity

Hinrichs

Kaiser

Paulos

et al. 2009

Blood

190

197

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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...

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“…Many cancers arise from the sites of infection, chronic irritation and inflammation as shown in Table 1, the inflammatory conditions are present before a malignant change occurs. To understand the kinetics and targets of inflammation in a discussion of T H 17 cells and cancer, the relationship between T H 1-derived IFN, T H 17 cells and antigen-presenting cells (APCs) in humans was recently studied (Kryczek et al, 2008a). These authors demonstrated in a cutting edge study that IFN could rapidly induce elevated B7-H1 expression on APCs and stimulate their production of IL-1 and IL-23.…”

Section: Association Of T H 17 Cells With Chronic Inflammationmentioning

confidence: 98%