Journal Articles

A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice

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Salomon et al. assessed the efficacy of a liposome-encapsulated single-stranded RNA vaccine encoding CD4+ T cell-recognized neoantigens in combination with local radiotherapy (LRT) in a murine CT26 colon carcinoma model. The CD4 neoantigen vaccine improved overall survival in a CD8+ T cell-dependent manner, and required cognate neoantigen CD4+ T cell help. CD4 neoantigen vaccine with LRT led to the rejection of gp70-negative CT26 tumors, demonstrating a poly-antigenic CD8+ T cell response, and protected mice against rechallenge. Anti-CTLA-4 antibody with vaccine/LRT further improved tumor rejection and survival of all mice bearing gp70-negative tumors.

Contributed by Shishir Pant

Salomon et al. assessed the efficacy of a liposome-encapsulated single-stranded RNA vaccine encoding CD4+ T cell-recognized neoantigens in combination with local radiotherapy (LRT) in a murine CT26 colon carcinoma model. The CD4 neoantigen vaccine improved overall survival in a CD8+ T cell-dependent manner, and required cognate neoantigen CD4+ T cell help. CD4 neoantigen vaccine with LRT led to the rejection of gp70-negative CT26 tumors, demonstrating a poly-antigenic CD8+ T cell response, and protected mice against rechallenge. Anti-CTLA-4 antibody with vaccine/LRT further improved tumor rejection and survival of all mice bearing gp70-negative tumors.

Contributed by Shishir Pant

ABSTRACT: Antigen-encoding, lipoplex-formulated RNA (RNA-LPX) enables systemic delivery to lymphoid compart- ments and selective expression in resident antigen-presenting cells. We report here that the rejection of CT26 tumors, mediated by local radiotherapy (LRT), is further augmented in a CD8+ T cell-dependent manner by an RNA-LPX vaccine that encodes CD4+ T cell-recognized neoantigens (CD4 neoantigen vaccine). Whereas CD8+ T cells induced by LRT alone were primarily directed against the immunodomi- nant gp70 antigen, mice treated with LRT plus the CD4 neoantigen vaccine rejected gp70-negative tumors and were protected from rechallenge with these tumors, indicating a potent poly-antigenic CD8+ T cell response and T cell memory. In the spleens of CD4 neoantigen-vaccinated mice, we found a high number of activated, poly-functional, Th1-like CD4+ T cells against ME1, the immunodominant CD4 neoantigen within the poly-neoantigen vaccine. LRT itself strongly increased CD8+ T cell numbers and clonal expansion. However, tumor infiltrates of mice treated with CD4 neoantigen vaccine/LRT, as compared to LRT alone, displayed a higher fraction of activated gp70-specific CD8+ T cells, lower PD-1/ LAG-3 expression and contained ME1-specific IFNγ+ CD4+ T cells capable of providing cognate help. CD4 neoantigen vaccine/LRT treatment followed by anti-CTLA-4 antibody therapy further enhanced the efficacy with complete remission of gp70-negative CT26 tumors and survival of all mice. Our data highlight the power of combining synergistic modes of action and warrants further exploration of the presented treatment schema.

Author Info: (a) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbH, 55131 Mainz, Germany; (b) BioNTech SE, 55131 Mainz, Germany; (c) Rese

Author Info: (a) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbH, 55131 Mainz, Germany; (b) BioNTech SE, 55131 Mainz, Germany; (c) Research Center for Immunotherapy (FZI) of the University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer

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Using anti-PD-L1 antibodies that selectively inhibit interactions between PD-L1 and PD-1, PD-L1 and B7-1 (in cis), or both, or alternatively, using mice with PD-L1 deficiency only in DCs (PD-L1ΔDC mice), only in macrophages, monocytes, and neutrophils, or with a global PD-L1 knockout, Oh et al. demonstrated that among intratumoral myeloid populations, PD-L1-expressing DCs play a crucial role in ultimately regulating antitumor T cell responses via PD-L1/B7-1 interactions in cis on DCs and PD-L1/PD-1 interactions between DCs and T cells. PD-L1ΔDC mice controlled tumors as effectively as PD-L1 KO mice, and PD-L1 blockade did not further improve the antitumor response. Thus, PD-1 axis blockade may play a role during T cell priming and expansion, in addition to reversing or preventing T cell exhaustion.

Using anti-PD-L1 antibodies that selectively inhibit interactions between PD-L1 and PD-1, PD-L1 and B7-1 (in cis), or both, or alternatively, using mice with PD-L1 deficiency only in DCs (PD-L1ΔDC mice), only in macrophages, monocytes, and neutrophils, or with a global PD-L1 knockout, Oh et al. demonstrated that among intratumoral myeloid populations, PD-L1-expressing DCs play a crucial role in ultimately regulating antitumor T cell responses via PD-L1/B7-1 interactions in cis on DCs and PD-L1/PD-1 interactions between DCs and T cells. PD-L1ΔDC mice controlled tumors as effectively as PD-L1 KO mice, and PD-L1 blockade did not further improve the antitumor response. Thus, PD-1 axis blockade may play a role during T cell priming and expansion, in addition to reversing or preventing T cell exhaustion.

ABSTRACT: Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1+ macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8+ T-cell responses. Our data identify a unique role for DCs in the PD-L1–PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1+ tumor cells.

Author Info: (1) Genentech, Inc., South San Francisco, CA, USA. (2) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) The Precision Immunology

Author Info: (1) Genentech, Inc., South San Francisco, CA, USA. (2) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Present address: Atreca, Inc., Redwood City, CA, USA. 6Present address: NGM Biopharmaceuticals, South San Francisco, CA, USA. e-mail: mellman.ira@gene.com

Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in patients with mesothelioma and mouse tumor models

LMB-100 is an immunotoxin targeting the cell surface protein mesothelin, which is highly expressed in many cancers including mesothelioma. Having observed that patients receiving pembrolizumab off protocol after LMB-100 treatment had increased tumor responses; we characterized these responses and developed animal models to study whether LMB-100 made tumors more responsive to antibodies blocking programmed cell death protein 1 (PD-1). The overall objective tumor response in the 10 patients who received PD-1 inhibitor (pembrolizumab, 9; nivolumab, 1) after progression on LMB-100 was 40%, and the median overall survival was 11.9 months. Of the seven evaluable patients, four had objective tumor responses, including one complete response and three partial responses, and the overall survival for these patients was 39.0+, 27.7, 32.6+, and 13.8 months. When stratified with regard to programmed death ligand 1 (PD-L1) expression, four of five patients with tumor PD-L1 expression had objective tumor response. Patients with positive tumor PD-L1 expression also had increased progression-free survival (11.3 versus 2.1 months, P = 0.0018) compared with those lacking PD-L1 expression. There was no statistically significant difference in overall survival (27.7 versus 6.8 months, P = 0.1). LMB-100 caused a systemic inflammatory response and recruitment of CD8(+) T cells in patients' tumors. The enhanced antitumor effects with LMB-100 plus anti-PD-1 antibody were also observed in a human peripheral blood mononuclear cell-engrafted mesothelioma mouse model and a human mesothelin-expressing syngeneic lung adenocarcinoma mouse model. LMB-100 plus pembrolizumab is now being evaluated in a prospective clinical trial for patients with mesothelioma.

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (2) Thorac

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (2) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (3) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (4) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (5) Developmental Therapeutics Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA. (6) Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (7) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (8) Department of Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD 20892, USA. (9) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (10) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (11) Biostatistics and Data Management Section, NCI, NIH, Bethesda, MD 20892, USA. (12) Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (13) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. hassanr@mail.nih.gov.

New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis

CD137 (4-1BB) is a surface glycoprotein that belongs to the tumour necrosis factor receptor family (TNFRSF9). Its expression is induced on activation on a number of leucocyte types. Interestingly, for cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals. Perturbation of CD137 by CD137L or agonist monoclonal antibodies on activated CD8 T cells protects such antigen-specific cytotoxic T lymphocytes from apoptosis, enhances effector functionalities and favours persistence and memory differentiation. As a consequence, agonist antibodies exert potent antitumour effects in mouse models and the CD137 signalling domain is critical in chimeric antigen receptors (CAR) of CAR T cells approved to be used in the clinic. New formats of CD137 agonist moieties are being clinically developed, seeking potent costimulation targeted to the tumour microenvironment to avoid liver inflammation side effects, that have thus far limited and delayed clinical development.

Author Info: (1) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain ietxeberria@alumni.unav.es. (2) Program of Immunology and Immunoth

Author Info: (1) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain ietxeberria@alumni.unav.es. (2) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain. (3) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain. (4) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain. Department of Immunology, Clinica Universidad de Navarra, Pamplona, Navarra, Spain.

The impact of immunotherapy on the survival of pancreatic adenocarcinoma patients who do not receive definitive surgery of the tumor

Background and Purpose: Immunotherapy has shown great efficacy in many cancers, but its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The objective of this study was to investigate the impact of immunotherapy on the overall survival of PDAC patients who did not receive definitive surgery of the pancreatic primary tumor site using the National Cancer Database (NCDB). Materials and Methods: Patients with pancreatic adenocarcinoma who did not receive surgery were identified from NCDB. Cox proportional hazard models were employed to assess the impact of immunotherapy on survival after adjusting for age at diagnosis, race, sex, place of living, income, education, treatment facility type, insurance status, year of diagnosis, and treatment types such as chemotherapy and radiation therapy. Results: Of 263,886 patients who were analyzed, 911 (0.35%) received immunotherapy. Among patients who received chemotherapy (101,546), and chemoradiation (30,226) therapy, 555/101,546 (0.55%) received chemotherapy plus immunotherapy, and 299/3,022 (9.9%) received chemoradiation plus immunotherapy. In a multivariable analysis adjusted for the factors mentioned above, immunotherapy was associated with significantly improved OS (HR: 0.866 (0.800-0.937); P < 0.001) compared to no immunotherapy. Chemotherapy plus immunotherapy was significantly associated with improved OS (HR: 0.848 (0.766-0.938); P < 0.001) compared to chemotherapy without immunotherapy. Further, chemoradiation plus immunotherapy was associated with significantly improved OS (HR: 0.813 (0.707-0.936); P < 0.001) compared to chemoradiation alone. Conclusion: In this study, the addition of immunotherapy to chemotherapy and chemoradiation therapy was associated with significantly improved OS in PDAC patients without definitive surgery. The study warrants future clinical trials of immunotherapy in PDAC.

Author Info: (1) Department of Radiation Oncology, University of Nebraska Medical Center, USA. (2) Department of Radiation Oncology, University of Nebraska Medical Center, USA. (3) Department o

Author Info: (1) Department of Radiation Oncology, University of Nebraska Medical Center, USA. (2) Department of Radiation Oncology, University of Nebraska Medical Center, USA. (3) Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, USA. (4) Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, USA. (5) Department of Radiation Oncology, University of Nebraska Medical Center, USA.

Novel MHC-Independent alphabetaTCRs Specific for CD48, CD102, and CD155 Self-Proteins and Their Selection in the Thymus

MHC-independent alphabetaTCRs (TCRs) recognize conformational epitopes on native self-proteins and arise in mice lacking both MHC and CD4/CD8 coreceptor proteins. Although naturally generated in the thymus, these TCRs resemble re-engineered therapeutic chimeric antigen receptor (CAR) T cells in their specificity for MHC-independent ligands. Here we identify naturally arising MHC-independent TCRs reactive to three native self-proteins (CD48, CD102, and CD155) involved in cell adhesion. We report that naturally arising MHC-independent TCRs require high affinity TCR-ligand engagements in the thymus to signal positive selection and that high affinity positive selection generates a peripheral TCR repertoire with limited diversity and increased self-reactivity. We conclude that the affinity of TCR-ligand engagements required to signal positive selection in the thymus inversely determines the diversity and self-tolerance of the mature TCR repertoire that is selected.

Author Info: (1) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (2) Experimental Immunology Branch, National Cancer Inst

Author Info: (1) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (2) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (3) Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD, United States. (4) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (5) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (6) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (7) Theodor Kocher Institute, Faculty of Bern, Universitat Bern, Bern, Switzerland. (8) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (9) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (10) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (11) Surgery Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (12) Surgery Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States. (13) Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD, United States. (14) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, United States.

PD1 gene polymorphism is associated with a poor prognosis in hepatocellular carcinoma following liver resection, cohort study

BACKGROUND: This study examined whether single nucleotide polymorphism (SNP) in programmed cell death protein (PD)-1 is related to the postoperative prognosis of patients with hepatocellular carcinoma (HCC). The immune checkpoint protein PD-1 is an important inhibitor of T cell responses. SNP in the promoter region of PD-1 -606G/A has been reported to result in high activation and expression of PD-1 associated with cancer risk. MATERIALS AND METHODS: We analyzed 321 patients with HCC who underwent hepatectomy between 2010 and 2015. PD-1 SNP was analyzed by polymerase chain reaction, and the prognosis after surgical treatment of patients with HCC was analyzed. RESULTS: The PD-1 SNP statuses were as follows: 90 AA (28.1%), 163GA (50.8%), 68GG (21.2%). The baseline parameters did not statistically differ between the three groups. The overall survival (OS) of patients with the GG genotype was significantly lower than that of those with the other genotypes (P=0.031). The GG genotype was an independent risk factor for OS (P=0.009; HR 2.201). There was no significant difference between the GG genotype and other genotypes in recurrent-free survival. The extrahepatic recurrence (EHR) rate of those with the GG genotype was significantly higher than that of those with the other genotypes (P=0.036). The GG genotype was an independent risk factor for EHR (P=0.008; HR 2.037). CONCLUSIONS: The PD-1 SNP GG genotype is associated with poor survival and increased EHR in HCC. Furthermore, the GG genotype is an independent predictive factor for OS and EHR.

Author Info: (1) Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatol

Author Info: (1) Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. (2) Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. Electronic address: tsukoba@hiroshima-u.ac.jp. (3) Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. (4) Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. (5) Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. (6) Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. (7) Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. (8) Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. (9) Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.

CD96, a new immune checkpoint, correlates with immune profile and clinical outcome of glioma

CD96 is a promising candidate for immunotherapy. However, its role and importance in glioma remains unknown. We thus aimed to genetically and clinically characterize CD96 expression in gliomas. For this, we extracted RNA-seq data of 699 glioma samples from the TCGA dataset and validated these findings using the CGGA dataset comprising 325 glioma samples. Clinical and isocitrate dehydrogenase (IDH) mutation status were also analyzed. Various packages in R language were mainly used for statistical analysis. CD96 expression was significantly up-regulated in high-grade, IDH-wildtype, and mesenchymal-molecular subtype gliomas based on TCGA data, which was validated using the CGGA dataset. Subsequent gene ontology analysis of both datasets suggested that genes relevant to CD96 are mainly involved in immune functions in glioma as such genes were positively correlated with CD96 expression. To further explore the relationship between CD96 and immune responses, we selected seven immune-related metagenes and found that CD96 expression was positively correlated with HCK, LCK, and MHC II in the CGGA and TCGA cohorts but negatively associated with IgG. Further, Pearson correlation analysis showed that CD96 is associated with TIGIT, CD226, CRTAM, TIM-3, PD-L1, CTLA-4, and STAT3, indicating the additive antitumoral effects of these checkpoint proteins. CD96 was also suggested to play an important role in immune responses and positively collaborate with other checkpoint members. These findings show that CD96 is promising candidate for immunotherapy, and that such agents could complement current immunotherapy strategies for glioma.

Author Info: (1) Department of Neurosurgery, Xiangya Hospital, Central South University, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. Clinical Diagnosis and Therap

Author Info: (1) Department of Neurosurgery, Xiangya Hospital, Central South University, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. Clinical Diagnosis and Therapy Center for Glioma of Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. (2) Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. Mental Health Institute of the Second Xiangya Hospital, Central South University, Chinese National Clinical Research Center on Mental Disorders (xiangya), Chinese National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, 410011, China. (3) Department of Neurosurgery, Xiangya Hospital, Central South University, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. Clinical Diagnosis and Therapy Center for Glioma of Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. (4) Director and Training and Exchange Cooperation Center, Orient Science & Technology College, Hunan Agricultural University, Changsha, Hunan, 410000, China. (5) Department of Neurosurgery, Xiangya Hospital, Central South University, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. Clinical Diagnosis and Therapy Center for Glioma of Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. (6) Department of Neurosurgery, Xiangya Hospital, Central South University, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. Clinical Diagnosis and Therapy Center for Glioma of Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. (7) Department of Neurosurgery, Xiangya Hospital, Central South University, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. Clinical Diagnosis and Therapy Center for Glioma of Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. (8) Department of Neurosurgery, Xiangya Hospital, Central South University, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. zhangliyang@csu.edu.cn. Clinical Diagnosis and Therapy Center for Glioma of Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. zhangliyang@csu.edu.cn.

MCL-1 is essential for survival but dispensable for metabolic fitness of FOXP3(+) regulatory T cells

FOXP3(+) regulatory T (Treg) cells are essential for maintaining immunological tolerance. Given their importance in immune-related diseases, cancer and obesity, there is increasing interest in targeting the Treg cell compartment therapeutically. New pharmacological inhibitors that specifically target the prosurvival protein MCL-1 may provide this opportunity, as Treg cells are particularly reliant upon this protein. However, there are two distinct isoforms of MCL-1; one located at the outer mitochondrial membrane (OMM) that is required to antagonize apoptosis, and another at the inner mitochondrial membrane (IMM) that is reported to maintain IMM structure and metabolism via ATP production during oxidative phosphorylation. We set out to elucidate the relative importance of these distinct biological functions of MCL-1 in Treg cells to assess whether MCL-1 inhibition might impact upon the metabolism of cells able to resist apoptosis. Conditional deletion of Mcl1 in FOXP3(+) Treg cells resulted in a lethal multiorgan autoimmunity due to the depletion of the Treg cell compartment. This striking phenotype was completely rescued by concomitant deletion of the apoptotic effector proteins BAK and BAX, indicating that apoptosis plays a pivotal role in the homeostasis of Treg cells. Notably, MCL-1-deficient Treg cells rescued from apoptosis displayed normal metabolic capacity. Moreover, pharmacological inhibition of MCL-1 in Treg cells resistant to apoptosis did not perturb their metabolic function. We conclude that Treg cells require MCL-1 only to antagonize apoptosis and not for metabolism. Therefore, MCL-1 inhibition could be used to manipulate Treg cell survival for clinical benefit without affecting the metabolic fitness of cells resisting apoptosis.

Author Info: (1) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC,

Author Info: (1) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (2) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (3) Cellular and Molecular Metabolism Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. School of Health Sciences, University of Tasmania, Launceston, TAS, Australia. (4) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (5) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (6) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (7) Cellular and Molecular Metabolism Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia. (8) The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, Australia. (9) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (10) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (11) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. dgray@wehi.edu.au. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. dgray@wehi.edu.au.

Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells

Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77(tg)) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Valpha14-Jalpha18 TCR-alpha chain gene into the Nur77(tg) (Nur77(tg);Valpha14(tg)) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-gamma-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.

Author Info: (1) Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, N

Author Info: (1) Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (2) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. Department of Chemistry and Life Science, US Military Academy, West Point, NY (3) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (4) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (5) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (6) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. Department of Biology, Caltech, Pasadena, CA 91125. (7) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. The Kennedy Institute of Rheumatology, University of Oxford, Oxford OX1 2JD, United Kingdom. (8) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (9) Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37232; sebastian.joyce@vumc.org. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.

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