Publications by authors named "Andrew L Mellor"

112 Publications

STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function.

Cell Mol Immunol 2021 Mar 26;18(3):632-643. Epub 2021 Jan 26.

Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA.

Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor- and self-DNA-elicited antitumor immunity and autoimmunity. However, STING can also suppress tumor immunity and autoimmunity. STING signaling in host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Host hematopoietic antigen-presenting cells (APCs) play key roles in donor T-cell priming during GVHD initiation. However, how STING regulates host hematopoietic APCs after allo-HCT remains unknown. We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs. STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT. Using bone marrow chimeras, we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease. Furthermore, STING on host CD11c cells played a dominant role in suppressing allogeneic T-cell responses. Mechanistically, STING deficiency resulted in increased survival, activation, and function of APCs, including macrophages and dendritic cells. Consistently, constitutive activation of STING attenuated the survival, activation, and function of APCs isolated from STING V154M knock-in mice. STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression, and migration into intestinal tissues, resulting in accelerated/exacerbated GVHD. Using pharmacologic approaches, we demonstrated that systemic administration of a STING agonist (bis-(3'-5')-cyclic dimeric guanosine monophosphate) to recipient mice before transplantation significantly reduced GVHD mortality. In conclusion, we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.
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http://dx.doi.org/10.1038/s41423-020-00611-6DOI Listing
March 2021

Exosome-derived miR-142-5p remodels lymphatic vessels and induces IDO to promote immune privilege in the tumour microenvironment.

Cell Death Differ 2021 Feb 14;28(2):715-729. Epub 2020 Sep 14.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.

Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8 T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-γ promoter, and enhances IFN-γ transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2-DNMT1-IFN-γ signalling to suppress and exhaust CD8 T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.
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http://dx.doi.org/10.1038/s41418-020-00618-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862304PMC
February 2021

Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity.

J Immunother Cancer 2020 08;8(2)

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK

Background: Activating the Stimulator of Interferon Genes (STING) adaptor incites antitumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signaling in the tumor microenvironment (TME) during development of Lewis lung carcinoma (LLC) suppresses antitumor immunity to promote tumor growth. We hypothesized that local immune balance favoring suppression of antitumor immunity also attenuates antitumor responses following STING activation. The purpose of this study was to evaluate how STING activation impacts antitumor responses in mice bearing LLC tumors.

Methods: Mice bearing established LLC tumors were treated with synthetic cyclic diadenyl monophosphate (CDA) to activate STING. Mice were monitored to assess LLC tumor growth, survival and protective antitumor immunity. Transcriptional and metabolic analyses were used to identify pathways responsive to CDA, and mice were co-treated with CDA and drugs that disrupt these pathways.

Results: CDA slowed LLC tumor growth but most CDA-treated mice (77%) succumbed to tumor growth. No evidence of tumor relapse was found in surviving CDA-treated mice at experimental end points but mice were not immune to LLC challenge. CDA induced rapid increase in immune regulatory pathways involving programmed death-1 (PD-1), indoleamine 2,3 dioxygenase (IDO) and cyclooxygenase-2 (COX2) in the TME. PD-1 blockade enhanced antitumor responses to CDA and increased mouse survival but mice did not eliminate primary tumor burdens. Two IDO inhibitor drugs had little or no beneficial effects on antitumor responses to CDA. A third IDO inhibitor drug synergized with CDA to enhance tumor control and survival but mice did not eliminate primary tumor burdens. In contrast, co-treatments with CDA and the COX2-selective inhibitor celecoxib controlled tumor growth, leading to uniform survival without relapse, and mice acquired resistance to LLC re-challenge and growth of distal tumors not exposed directly to CDA. Thus, mice co-treated with CDA and celecoxib acquired stable and systemic antitumor immunity.

Conclusions: STING activation incites potent antitumor responses and boosts local immune regulation to attenuate antitumor responses. Blocking STING-responsive regulatory pathways synergizes with CDA to enhance antitumor responses, particularly COX2 inhibition. Thus, therapy-induced resistance to STING may necessitate co-treatments to disrupt regulatory pathways responsive to STING in patients with cancer.
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http://dx.doi.org/10.1136/jitc-2020-001182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451475PMC
August 2020

Co-treatments to Boost IDO Activity and Inhibit Production of Downstream Catabolites Induce Durable Suppression of Experimental Autoimmune Encephalomyelitis.

Front Immunol 2020 17;11:1256. Epub 2020 Jun 17.

Immune Metabolism Laboratory, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.

Reinforcing defective tolerogenic processes slows progression of autoimmune (AI) diseases and has potential to promote drug-free disease remission. Previously, we reported that DNA nanoparticles (DNPs) and cyclic dinucleotides (CDNs) slow progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, by activating the Stimulator of Interferon Genes (STING) signaling adaptor to stimulate interferon type 1 (IFN-I) production, which induced dendritic cells to express indoleamine 2,3 dioxygenase (IDO) and acquire immune regulatory phenotypes. Here, we show that therapeutic responses to DNPs depend on DNA sensing via cyclic GAMP synthase (cGAS) and interactions between Programmed Death-1 (PD-1) and PD-1 ligands. To investigate how increased tryptophan (Trp) metabolism by IDO promotes therapeutic responses mice were co-treated at EAE onset with DNPs and drugs that inhibit kynurenine aminotransferase-II (KatII) or 3-hydroxyanthranilic acid dioxygenase (HAAO) activity downstream of IDO in the kynurenine (Kyn) pathway. DNP and KatII or HAAO inhibitor co-treatments suppressed EAE progression more effectively than DNPs, while KatII inhibition had no significant therapeutic benefit and HAAO inhibition attenuated but did not prevent EAE progression. Moreover, therapeutic responses to co-treatments were durable as EAE progression did not resume after co-treatment. Thus, using STING agonists to boost IDO activity and manipulating the Kyn pathway downstream of IDO is an effective strategy to enhance tolerogenic responses that overcome autoimmunity to suppress EAE progression.
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http://dx.doi.org/10.3389/fimmu.2020.01256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311583PMC
June 2020

CD40 Accelerates the Antigen-Specific Stem-Like Memory CD8 T Cells Formation and Human Papilloma Virus (HPV)-Positive Tumor Eradication.

Front Immunol 2020 27;11:1012. Epub 2020 May 27.

Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangdong Provincial Key Laboratory of Proteomics, Guangzhou, China.

Antigen-specific stem-like memory CD8 T cells (Tscm) have a series of stem cell characteristics, including long-term survival, self-renewal, anti-apoptosis and persistent differentiation into cytotoxic T cells. The effective induction of tumor-specific CD8 Tscm could persistently eradicate tumor in pro-tumor hostile microenvironment. This study was to investigate the role of CD40 in HPV16-specific CD8 Tscm induction and its anti-tumor function. We found that CD40 activation accelerated vaccine-induced HPV16 E7-specific CD8 Tscm formation. Comparing to other HPV-specific CD8 T cells, CD8 Tscm were found to be stronger and long-term anti-tumor function, and , even in the adoptive cellular transferring model. Furthermore, high frequencies of Tscm might prevent the HPV infection to move on to the development of cancer. And the CD40 effect on Tscm involved Wnt/β-catenin activation. Our study suggest that CD40 activation supports the generation of tumor-specific CD8 Tscm, thus providing new insight into cancer immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2020.01012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267052PMC
May 2020

Novel delivery of cellular therapy to reduce ischemia reperfusion injury in kidney transplantation.

Am J Transplant 2020 Jun 7. Epub 2020 Jun 7.

NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK.

Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC ) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP. Pairs (5) of human kidneys, from the same donor, were simultaneously perfused for 7 hours. Kidneys were randomly allocated to receive MAPC treatment or control. Serial samples of perfusate, urine, and tissue biopsies were taken for comparison. MAPC-treated kidneys demonstrated improved urine output (P = .009), decreased expression of injury biomarker NGAL (P = .012), improved microvascular perfusion on contrast-enhanced ultrasound (cortex P = .019, medulla P = .001), downregulation of interleukin (IL)-1β (P = .050), and upregulation of IL-10 (P < .047) and Indolamine-2, 3-dioxygenase (P = .050). A chemotaxis model demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (P < .001). Immunofluorescence revealed prelabeled MAPC cells in the perivascular space of kidneys during NMP. We report the first successful delivery of cellular therapy to a human kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to transplantation.
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http://dx.doi.org/10.1111/ajt.16100DOI Listing
June 2020

CD73 on cancer-associated fibroblasts enhanced by the A-mediated feedforward circuit enforces an immune checkpoint.

Nat Commun 2020 01 24;11(1):515. Epub 2020 Jan 24.

Department of Biochemistry and Molecular Biology, Cancer Immunology, Inflammation & Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA.

CD73, an ecto-5'-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73 population in human colorectal cancers (CRCs) and two CD73 murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A and A pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A-mediated ADO-CAF-CD73 feedforward circuit and A-mediated immune suppression is crucial for improving therapeutic outcomes.
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http://dx.doi.org/10.1038/s41467-019-14060-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981126PMC
January 2020

Stimulator of interferon genes agonists attenuate type I diabetes progression in NOD mice.

Immunology 2019 12 15;158(4):353-361. Epub 2019 Oct 15.

Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK.

Reagents that activate the signaling adaptor stimulator of interferon genes (STING) suppress experimentally induced autoimmunity in murine models of multiple sclerosis and arthritis. In this study, we evaluated STING agonists as potential reagents to inhibit spontaneous autoimmune type I diabetes (T1D) onset in non-obese diabetic (NOD) female mice. Treatments with DNA nanoparticles (DNPs), which activate STING when cargo DNA is sensed, delayed T1D onset and reduced T1D incidence when administered before T1D onset. DNP treatment elevated indoleamine 2,3 dioxygenase (IDO) activity, which regulates T-cell immunity, in spleen, pancreatic lymph nodes and pancreas of NOD mice. Therapeutic responses to DNPs were partially reversed by inhibiting IDO and DNP treatment synergized with insulin therapy to further delay T1D onset and reduce T1D incidence. Treating pre-diabetic NOD mice with cyclic guanyl-adenyl dinucleotide (cGAMP) to activate STING directly delayed T1D onset and stimulated interferon-αβ (IFN-αβ), while treatment with cyclic diguanyl nucleotide (cdiGMP) did not delay T1D onset or induce IFN-αβ in NOD mice. DNA sequence analyses revealed that NOD mice possess a STING polymorphism that may explain differential responses to cGAMP and cdiGMP. In summary, STING agonists attenuate T1D progression and DNPs enhance therapeutic responses to insulin therapy.
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http://dx.doi.org/10.1111/imm.13122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856934PMC
December 2019

Limited Effect of Indolamine 2,3-Dioxygenase Expression and Enzymatic Activity on Lupus-Like Disease in B6.Nba2 Mice.

Front Immunol 2019 27;10:2017. Epub 2019 Aug 27.

Cleveland Clinic Foundation, Department of Immunology, Lerner Research Institute, Cleveland, OH, United States.

B6.Nba2 mice spontaneously develop a lupus-like disease characterized by elevated levels of serum anti-nuclear autoantibody (ANA) immune complexes and constitutive type I interferon (IFNα) production. During disease progression, both plasmacytoid dendritic cells (pDCs) and antibody secreting plasma cells accumulate in spleens of B6.Nba2 mice. Indoleamine 2,3-dioxygenase (IDO) has been suggested to play a role in several autoimmune diseases including in the MRL/lpr model of mouse lupus-like disease; however, it remains unknown if IDO is involved in disease development and/or progression in other spontaneous models. We show here that IDO1 protein and total IDO enzymatic activity are significantly elevated in lupus-prone B6.Nba2 mice relative to B6 controls. IDO1 expression was restricted to PCs and SignR1 macrophages in both strains, while significantly increased in B6.Nba2-derived SiglecH (SigH) pDCs. Despite this unique expression pattern, neither pharmacologic inhibition of total IDO nor IDO1 gene ablation altered serum autoantibody levels, splenic immune cell activation pattern, or renal inflammation in B6.Nba2 mice. Interestingly, IDO pharmacologic inhibition, but not IDO1 deficiency, resulted in diminished complement factor C'3 fixation to kidney glomeruli, suggesting a possible therapeutic benefit of IDO inhibition in SLE patients with renal involvement.
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http://dx.doi.org/10.3389/fimmu.2019.02017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727869PMC
October 2020

A Validation Study on IDO Immune Biomarkers for Survival Prediction in Non-Small Cell Lung Cancer: Radiation Dose Fractionation Effect in Early-Stage Disease.

Clin Cancer Res 2020 01 30;26(1):282-289. Epub 2019 Aug 30.

Department of Radiation Oncology, University Hospitals Cleveland Medical Center/Seidman Cancer Center, Cleveland, Ohio.

Purpose: We recently reported that indoleamine 2, 3-dioxygenase (IDO) activity is significantly correlated with more distant metastasis and worse survival. The present study examined whether radiotherapy (RT) dose fractionation correlates with IDO-mediated immune activity in patients with early-stage NSCLC. Patients with newly diagnosed stage I-II NSCLC treated with either conventionally fractionated 3-dimensional conformal radiotherapy (3DCRT) or stereotactic body radiotherapy (SBRT) were analyzed. Levels of two key molecules associated with the IDO immune checkpoint, serum kynurenine and the kynurenine:tryptophan ratio (K:T ratio), were measured at pre-RT, during-RT, and 3-month post-RT. The relationship between disease control outcomes [overall survival (OS), progression free survival, and local/regional/distant failure rates] and absolute levels of these markers, as well as dynamic changes in their levels during RT, was studied.

Results: Fifty-six patients (SBRT = 28, 3DCRT = 28) with early-stage NSCLC were studied. In all patients, higher kynurenine post-RT was significantly associated with worse OS ([HR, 1.25; 95% confidence interval (CI), 1.01-1.55; = 0.044). No statistically significant differences in absolute kynurenine levels or the K:T ratio were observed in patients treated with 3DCRT or SBRT at any of the three time points. However, the absolute kynurenine levels rose significantly more post-RT in the 3DCRT patients with a median increase 0.721 ng/mL, compared to that of SBRT patients (0.115 ng/mL); = 0.022.

Conclusions: This study validated that elevated IDO activity correlated with worse survival outcomes in patients with early-stage NSCLC treated with definitive RT. Hypofractionated SBRT may have less immunosuppressive effect than 3DCRT, as measured by IDO.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1202DOI Listing
January 2020

Adoptive CD8 T cell therapy against cancer:Challenges and opportunities.

Cancer Lett 2019 Oct 26;462:23-32. Epub 2019 Jul 26.

Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangdong Provincial Key Laboratory of Proteomics, Guangzhou, Guangdong, People's Republic of China. Electronic address:

Cancer immunotherapy is a new and promising option for cancer treatment. Unlike traditional chemo- and radiotherapy, immunotherapy actives host immune system to attack malignancies, and this potentially offers long-term protection from recurrence with less toxicity in comparison to conventional chemo- and radiation therapy. In adoptive CD8 T cell therapy (ACT), large numbers of tumor-specific T cells are sourced from patients and expanded in vitro and infused back to patients. T cells can be expanded from naturally-induced tumor-specific CD8 T cells isolated from tumor infiltrating lymphocytes (TIL) or genetically-modified autologous circulating CD8 T cells. The engineered T cells expressed tumor-specific antigen receptors including chimeric antigen receptors (CARs) and T cell receptors (TCRs), prepared from cultured B and T cell clones, respectively. The most successful ACT, anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy directed against B cell lymphoma, is already approved for use based on evidence of efficacy. Efficacy of solid tumors is not yet forthcoming. This review summarizes current technology developments using ACT in clinical trials. In this review, differences between various ACT approaches are discussed. Furthermore, resistance factors in the tumor microenvironment are also considered, as are immune related adverse effects, critical clinic monitoring parameters and potential mitigation approaches.
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http://dx.doi.org/10.1016/j.canlet.2019.07.017DOI Listing
October 2019

Immune control by amino acid catabolism during tumorigenesis and therapy.

Nat Rev Cancer 2019 03;19(3):162-175

Institute of Cellular Medicine, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle-upon-Tyne, UK.

Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer. Cells catabolizing Trp and Arg suppress effector T cells and stabilize regulatory T cells to suppress immunity in chronic inflammatory diseases of clinical importance, including cancers. Processes that induce Trp and Arg catabolism in the TME remain incompletely defined. Indoleamine 2,3 dioxygenase (IDO) and arginase 1 (ARG1), which catabolize Trp and Arg, respectively, respond to inflammatory cues including interferons and transforming growth factor-β (TGFβ) cytokines. Dying cells generate inflammatory signals including DNA, which is sensed to stimulate the production of type I interferons via the stimulator of interferon genes (STING) adaptor. Thus, dying cells help establish local conditions that suppress antitumour immunity to promote tumorigenesis. Here, we review evidence that Trp and Arg catabolism contributes to inflammatory processes that promote tumorigenesis, impede immune responses to therapy and might promote neurological comorbidities associated with cancer.
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http://dx.doi.org/10.1038/s41568-019-0106-zDOI Listing
March 2019

Metabolic requirements for expanding and arming a clone army.

Nat Immunol 2019 02;20(2):118-120

Institute of Cellular Medicine, Newcastle University, Newcastle, UK.

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http://dx.doi.org/10.1038/s41590-018-0299-4DOI Listing
February 2019

Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?

Front Immunol 2017 27;8:1360. Epub 2017 Oct 27.

Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Cells expressing IDO suppress innate and adaptive immunity to promote tolerance by catabolizing the amino acid tryptophan (Trp) and other indole compounds. Interferon type I (IFN-I) and type II (IFN-II) produced at sites of inflammation or by activated immune cells are potent IDO inducers because mammalian IDO genes contain IFN response elements. Elevated IDO expression by dendritic cells (DCs) is of particular significance because IDO activity converts mature DCs into tolerogenic APCs that suppress effector T cells (Teff) and promote regulatory T cells (Tregs), thereby promoting tolerance. Local Trp depletion and production of immune suppressive Trp catabolites contribute to tolerogenic processes by activating metabolic pathways responsive to amino acid withdrawal and aryl hydrocarbon signaling, respectively. Sustained IDO elevation creates local immune privilege that protects tissues from immune-mediated damage and allows tissues to heal. This response occurs in lymphoid tissues when DNA released by dying tissue cells is sensed to induce specialized DC subsets to acquire tolerogenic phenotypes. The tolerogenic effects of IDO also promote tumorigenesis and help establish immune checkpoints in cancer, as malignant cells are protected from immune surveillance. Similar processes may attenuate host immunity to some pathogens that persist in immunocompetent individuals. However, if inflammation with IDO involvement is not resolved, chronic immune activation at such sites causes progressive tissue damage over time. Another effect of sustained IDO activity is enhanced pain sensitivity, as some Trp catabolites produced by cells expressing IDO are neuroactive. In this review, we summarize links between IDO and chronic inflammatory diseases and discuss prospects for exploiting IDO and Trp catabolism to suppress immunity and promote tolerance for clinical benefit, with particular emphasis on protecting tissues from destructive autoimmunity.
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http://dx.doi.org/10.3389/fimmu.2017.01360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663846PMC
October 2017

IDO Immune Status after Chemoradiation May Predict Survival in Lung Cancer Patients.

Cancer Res 2018 02 8;78(3):809-816. Epub 2017 Nov 8.

Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.

Host immunity influences the impact of radiotherapy (RT) in cancer, but mechanistic connections remain obscure. In this study, we investigated the relationship of indoleamine 2,3-dioxygenase (IDO) systemic activity on clinical outcomes in RT-treated non-small cell lung cancer (NSCLC). IDO-mediated production of kynurenine and the kynurenine:tryptophan ratio in patient blood serum were determined for stage III NSCLC patients at times before, during, and after RT administration and then correlated to overall survival (OS), progression-free survival, and disease progression rate in patients. We found the impact of RT on these serum IDO markers to be heterogeneous in patients. On average, kynurenine:tryptophan ratios were reduced during RT but restored after RT. Notably, both baseline levels of kynurenine:tryptophan and changes in the levels of kynurenine after RT were significantly associated with OS. When combined, favorable change and favorable baseline corresponded with very long-term OS (median OS was not reached after 57 months of median follow-up). Favorable change combined with unfavorable baseline still corresponded with a lack of distant metastases. Our results suggest that RT alters IDO-mediated immune status in NSCLC patients and that changes in this serum biomarker may be useful to predict outcomes and perhaps personalize RT dosage to improve survival. Radiotherapy appears to influence systemic IDO activity and to exert a significant impact on metastatic risk and overall survival, with possible implications for defining a biomarker to optimize radiation dose in patients to improve outcomes. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811356PMC
February 2018

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14 Monocytes.

J Immunol 2017 03 13;198(6):2286-2301. Epub 2017 Feb 13.

Research Department, Argos Therapeutics, Inc., Durham, NC 27704;

The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified. In this article, we identify myeloid differentiation factor-2 (MD-2), the coreceptor within the TLR4/MD-2 receptor complex, as the high-affinity sCD83 binding partner. TLR4/MD-2 mediates proinflammatory signal delivery following recognition of bacterial LPSs. However, altering TLR4 signaling can attenuate the proinflammatory cascade, leading to LPS tolerance. Our data show that binding of sCD83 to MD-2 alters this signaling cascade by rapidly degrading IL-1R-associated kinase-1, leading to induction of the anti-inflammatory mediators IDO, IL-10, and PGE in a COX-2-dependent manner. sCD83 inhibited T cell proliferation, blocked IL-2 secretion, and rendered T cells unresponsive to further downstream differentiation signals mediated by IL-2. Therefore, we propose the tolerogenic mechanism of action of sCD83 to be dependent on initial interaction with APCs, altering early cytokine signal pathways and leading to T cell unresponsiveness.
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http://dx.doi.org/10.4049/jimmunol.1600802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337811PMC
March 2017

Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase.

PLoS Pathog 2016 05 11;12(5):e1005615. Epub 2016 May 11.

Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Augusta University, Augusta, Georgia, United States of America.

Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.
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http://dx.doi.org/10.1371/journal.ppat.1005615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863962PMC
May 2016

Deletion of LRP5 and LRP6 in dendritic cells enhances antitumor immunity.

Oncoimmunology 2016 Apr 14;5(4):e1115941. Epub 2015 Dec 14.

Cancer Immunology, Inflammation and Tolerance Program, GRU Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.

The tumor microenvironment (TME) contains high levels of the Wnt family of ligands, and aberrant Wnt-signaling occurs in many tumors. Past studies have been directed toward how the Wnt signaling cascade regulates cancer development, progression and metastasis. However, its effects on host antitumor immunity remain unknown. In this report, we show that Wnts in the TME condition dendritic cells (DCs) to a regulatory state and suppress host antitumor immunity. DC-specific deletion of Wnt co-receptors low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in mice markedly delayed tumor growth and enhanced host antitumor immunity. Mechanistically, loss of LRP5/6-mediated signaling in DCs resulted in enhanced effector T cell differentiation and decreased regulatory T cell differentiation. This was due to increased production of pro-inflammatory cytokines and decreased production of IL-10, TGF-β1 and retinoic acid (RA). Likewise, pharmacological inhibition of the Wnts' interaction with its cognate co-receptors LRP5/6 and Frizzled (Fzd) receptors had similar effects on tumor growth and effector T cell responses. Moreover, blocking Wnt-signaling in DCs resulted in enhanced capture of tumor-associated antigens and efficient cross-priming of CD8 T cells. Hence, blocking the Wnt pathway represents a potential therapeutic to overcome tumor-mediated immune suppression and augment antitumor immunity.
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http://dx.doi.org/10.1080/2162402X.2015.1115941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839371PMC
April 2016

STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation.

Cancer Res 2016 04 10;76(8):2076-81. Epub 2016 Mar 10.

Cancer Immunology, Inflammation and Tolerance Program and Department of Medicine, Augusta University, Augusta, Georgia.

Cytosolic DNA sensing is an important process during the innate immune response that activates the stimulator of interferon genes (STING) adaptor and induces IFN-I. STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists, and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). Although STING also induced IDO in tumor-draining lymph nodes (TDLN) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8(+) T-cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL10 production in the TME. Depletion of CD8(+) T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8(+) T-cell effector functions during tumorigenesis. In contrast with native LLC tumors, STING signaling neither promoted growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity and how IDO inhibition can overcome this state by attenuating tumor tolerance. Furthermore, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials. Cancer Res; 76(8); 2076-81. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873329PMC
April 2016

IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance.

Trends Immunol 2016 Mar 31;37(3):193-207. Epub 2016 Jan 31.

Institute of Cellular Medicine, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. Electronic address:

Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated with tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area.
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http://dx.doi.org/10.1016/j.it.2016.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916957PMC
March 2016

The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment.

Sci Adv 2015 Nov 6;1(10):e1500845. Epub 2015 Nov 6.

Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.

The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.
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http://dx.doi.org/10.1126/sciadv.1500845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640592PMC
November 2015

Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.

J Immunol 2015 Jun 15;194(12):5713-24. Epub 2015 May 15.

Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and

Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy.
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http://dx.doi.org/10.4049/jimmunol.1500277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458436PMC
June 2015

Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation.

J Immunol 2015 Apr 20;194(7):3295-304. Epub 2015 Feb 20.

Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;

Breakdown in immunological tolerance to self-Ags or uncontrolled inflammation results in autoimmune disorders. Dendritic cells (DCs) play an important role in regulating the balance between inflammatory and regulatory responses in the periphery. However, factors in the tissue microenvironment and the signaling networks critical for programming DCs to control chronic inflammation and promote tolerance are unknown. In this study, we show that wnt ligand-mediated activation of β-catenin signaling in DCs is critical for promoting tolerance and limiting neuroinflammation. DC-specific deletion of key upstream (lipoprotein receptor-related protein [LRP]5/6) or downstream (β-catenin) mediators of canonical wnt signaling in mice exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of LRP5/6-β-catenin-mediated signaling in DCs led to an increased Th1/Th17 cell differentiation but reduced regulatory T cell response. This was due to increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines such as IL-10 and IL-27 by DCs lacking LRP5/6-β-catenin signaling. Consistent with these findings, pharmacological activation of canonical wnt/β-catenin signaling delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology. Thus, the activation of canonical wnt signaling in DCs limits effector T cell responses and represents a potential therapeutic approach to control autoimmune neuroinflammation.
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http://dx.doi.org/10.4049/jimmunol.1402691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369436PMC
April 2015

β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells.

Cancer Res 2015 Feb 7;75(4):656-665. Epub 2015 Jan 7.

Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.

Tumors actively suppress antitumor immunity, creating formidable barriers to successful cancer immunotherapy. The molecular mechanisms underlying tumor-induced immune tolerance are largely unknown. In the present study, we show that dendritic cells (DC) in the tumor microenvironment acquire the ability to metabolize vitamin A to produce retinoic acid (RA), which drives regulatory T-cell responses and immune tolerance. Tolerogenic responses were dependent on induction of vitamin A-metabolizing enzymes via the β-catenin/T-cell factor (TCF) pathway in DCs. Consistent with this observation, DC-specific deletion of β-catenin in mice markedly reduced regulatory T-cell responses and delayed melanoma growth. Pharmacologic inhibition of either vitamin A-metabolizing enzymes or the β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and regulatory T-cell responses. Hence, β-catenin/TCF4 signaling induces local regulatory DC and regulatory T-cell phenotypes via the RA pathway, identifying this pathway as an important target for anticancer immunotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333068PMC
February 2015

Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells.

J Immunol 2015 Feb 5;194(4):2011-21. Epub 2015 Jan 5.

Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and

In recent years, the immune-potentiating effects of some widely used chemotherapeutic agents have been increasingly appreciated. This provides a rationale for combining conventional chemotherapy with immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicated the immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiple myeloma, but the underlying mechanisms remain obscure. In the present study, we investigated the impact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specific CD4(+) T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst of inflammatory cytokines and chemokines during the cellular recovery phase after melphalan-induced myelodepletion and leukodepletion. After melphalan treatment, tumor cells exhibited characteristics of immunogenic cell death, including membrane translocation of the endoplasmic reticulum-resident calreticulin and extracellular release of high-mobility group box 1. Additionally, there was enhanced tumor Ag uptake by dendritic cells in the tumor-draining lymph node. Consistent with these immunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of the endogenous CD8(+) T cells and, more importantly, effectively drove the clonal expansion and effector differentiation of adoptively transferred tumor-specific CD4(+) T cells. Notably, the combination of melphalan and CD4(+) T cell adoptive cell therapy was more efficacious than either treatment alone in prolonging the survival of mice with advanced B cell lymphomas or colorectal tumors. These findings provide mechanistic insights into melphalan's immunostimulatory effects and demonstrate the therapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4(+) T cells.
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http://dx.doi.org/10.4049/jimmunol.1401894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324150PMC
February 2015

STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy?

Expert Rev Clin Immunol 2015 Jan 18;11(1):155-65. Epub 2014 Dec 18.

Cancer immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, 1120 15th St, Augusta GA 30912, USA.

DNA has potent immunogenic properties that are useful to enhance vaccine efficacy. DNA also incites hyperinflammation and autoimmunity if DNA sensing is not regulated. Paradoxically, DNA regulates immunity and autoimmunity when administered systemically as DNA nanoparticles. DNA nanoparticles regulated immunity via cytosolic DNA sensors that activate the signaling adaptor stimulator of interferon genes. In this review, we describe how DNA sensing to activate stimulator of interferon genes promotes regulatory responses and discuss the biological and clinical implications of these responses for understanding disease progression and designing better therapies for patients with chronic inflammatory diseases, such as autoimmune syndromes or cancer.
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http://dx.doi.org/10.1586/1744666X.2015.995097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387570PMC
January 2015

TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation.

J Immunol 2014 Oct 10;193(8):4203-13. Epub 2014 Sep 10.

Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and

Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1, which recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. In this study, we show that TLR2 signaling via AKT activates the β-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/T cell factor 4 was critical to induce regulatory molecules IL-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress proinflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.
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http://dx.doi.org/10.4049/jimmunol.1400614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185231PMC
October 2014

Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA.

Eur J Immunol 2014 Oct 25;44(10):2847-53. Epub 2014 Aug 25.

Cancer immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA, USA.

DNA is immunogenic and many cells express cytosolic DNA sensors that activate the stimulator of interferon genes (STING) adaptor to trigger interferon type I (IFN-β) release, a potent immune activator. DNA sensing to induce IFN-β triggers host immunity to pathogens but constitutive DNA sensing can induce sustained IFN-β release that incites autoimmunity. Here, we focus on cytosolic DNA sensing via the STING/IFN-β pathway that regulates immune responses. Recent studies reveal that cytosolic DNA sensing via the STING/IFN-β pathway induces indoleamine 2,3 dioxygenase (IDO), which catabolizes tryptophan to suppress effector and helper T-cell responses and activate Foxp3-lineage CD4(+) regulatory T (Treg) cells. During homeostasis, and in some inflammatory settings, specialized innate immune cells in the spleen and lymph nodes may ingest and sense cytosolic DNA to reinforce tolerance that prevents autoimmunity. However, malignancies and pathogens may exploit DNA-induced regulatory responses to suppress natural and vaccine-induced immunity to malignant and infected cells. In this review, we discuss the biologic significance of regulatory responses to DNA and novel approaches to exploit DNA-induced immune responses for therapeutic benefit. The ability of DNA to drive tolerogenic or immunogenic responses highlights the need to evaluate immune responses to DNA in physiologic settings relevant to disease progression or therapy.
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http://dx.doi.org/10.1002/eji.201344407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197080PMC
October 2014

The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma.

J Immunother Cancer 2014 7;2:21. Epub 2014 Jul 7.

GRU Cancer Center, Georgia Regents University, Augusta, Georgia, 30912, USA ; Program in Cancer immunology, Inflammation and Tolerance (CIT), Georgia Regents University, Augusta, GA, USA ; Medical College of Georgia Department of Pediatrics, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA CN-4141A, USA.

Background: Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction.

Methods: To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy.

Results: Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival.

Conclusions: Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.
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http://dx.doi.org/10.1186/2051-1426-2-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105871PMC
July 2014