Faculty Opinions recommendation of Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension.

Abstract Glioblastoma (GBM) is refractory to current T cell-based immunotherapies such as checkpoint blockade. GBM is characterized by extensive infiltration of immunosuppressive macrophages that contribute to the treatment resistance. Here we develop a dual-targeting strategy to synergistically activate tumor-associated macrophages (Mφs), which efficiently overcomes GBM resistance to therapeutic blockade of the PD1 and CTLA4 checkpoints. Consistent with a pro-tumor role of IL-6 in alternative Mφ polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mφs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mφs. Combination of IL-6 inhibition with CD40 stimulation reverses Mφ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models. Notably, this antibody cocktail-based combination immunotherapy with checkpoint blockade almost doubles animal survival in the genetically engineered mouse GBM model and induces complete tumor regression in the GL261 model. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting therapeutic opportunities for GBM.

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Negative regulation of mTOR activation by diacylglycerol kinases

Blood ◽

10.1182/blood-2010-08-300731 ◽

2011 ◽

Vol 117 (15) ◽

pp. 4022-4031 ◽

Cited By ~ 70

Author(s):

Balachandra K. Gorentla ◽

Chi-Keung Wan ◽

Xiao-Ping Zhong

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mitogen Activated Protein Kinase ◽

Effector Memory ◽

Multiple Characteristic ◽

Genetic Ablation ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Constitutively Active

Abstract The engagement of TCR induces T-cell activation, which initiates multiple characteristic changes such as increase in cell size, cell division, and the production of cytokines and other effector molecules. The mammalian target of rapamycin (mTOR) regulates protein synthesis, transcription, cell survival, and autophagy. Critical roles of mTOR in T-cell activation and effector/memory differentiation have been revealed using chemical inhibitors or by genetic ablation of mTOR in T cells. However, the connection between mTOR signaling and other signaling cascades downstream of TCR is unclear. We demonstrate that diacylglycerol (DAG) and TCR engagement activate signaling in both mTOR complexes 1 and 2 through the activation of the Ras–mitogen-activated protein kinase/extracellular signal–regulated kinase 1/2 (Mek1/2)–extracellular signal–regulated kinase 1/2 (Erk1/2)–activator protein 1 (AP-1), known collectively as the Ras-Mek1/2-Erk1/2-AP-1 pathway. Deficiency of RasGRP1 or inhibition of Mek1/2 activity drastically decreases TCR-induced mTOR activation, whereas constitutively active Ras or Mek1 promotes mTOR activation. Although constitutively active Akt promotes TCR-induced mTOR activation, such activation is attenuated by Mek1/2 inhibition. We demonstrated further that DAG kinases (DGKs) α and ζ, which terminate DAG-mediated signaling, synergistically inhibit TCR-induced mTOR activation by inhibiting the Ras-Mek1/2-Erk/12 pathway. These observations provide novel insights into the regulation of mTOR activation.

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The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease

Journal of Experimental Medicine ◽

10.1084/jem.20081219 ◽

2008 ◽

Vol 205 (9) ◽

pp. 2005-2017 ◽

Cited By ~ 255

Author(s):

Mark M.W. Chong ◽

Jeffrey P. Rasmussen ◽

Alexander Y. Rudensky ◽

Dan R. Littman

Keyword(s):

T Cell ◽

Inflammatory Disease ◽

Cell Types ◽

Mirna Biogenesis ◽

Cell Compartment ◽

Foxp3 Gene ◽

Genetic Ablation ◽

And Function ◽

Specific Deletion

MicroRNAs (miRNAs) are implicated in the differentiation and function of many cell types. We provide genetic and in vivo evidence that the two RNaseIII enzymes, Drosha and Dicer, do indeed function in the same pathway. These have previously been shown to mediate the stepwise maturation of miRNAs (Lee, Y., C. Ahn, J. Han, H. Choi, J. Kim, J. Yim, J. Lee, P. Provost, O. Radmark, S. Kim, and V.N. Kim. 2003. Nature. 425:415–419), and genetic ablation of either within the T cell compartment, or specifically within Foxp3+ regulatory T (T reg) cells, results in identical phenotypes. We found that miRNA biogenesis is indispensable for the function of T reg cells. Specific deletion of either Drosha or Dicer phenocopies mice lacking a functional Foxp3 gene or Foxp3+ cells, whereas deletion throughout the T cell compartment also results in spontaneous inflammatory disease, but later in life. Thus, miRNA-dependent regulation is critical for preventing spontaneous inflammation and autoimmunity.

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Genetic ablation or pharmacological blockade of dipeptidyl peptidase IV does not impact T cell-dependent immune responses

BMC Immunology ◽

10.1186/1471-2172-10-19 ◽

2009 ◽

Vol 10 (1) ◽

pp. 19 ◽

Cited By ~ 35

Author(s):

Kalpit A Vora ◽

Gene Porter ◽

Roche Peng ◽

Yan Cui ◽

Kellyann Pryor ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Genetic Ablation ◽

Pharmacological Blockade

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Tumors induce de novo steroid biosynthesis in T cells to evade immunity

10.1101/471359 ◽

2018 ◽

Cited By ~ 1

Author(s):

Bidesh Mahata ◽

Jhuma Pramanik ◽

Louise van der Weyden ◽

Krzysztof Polanski ◽

Gozde Kar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Tumor Immunity ◽

Cell Function ◽

Immune Cell ◽

De Novo ◽

Steroid Biosynthesis ◽

Genetic Ablation ◽

Tumor Immunosuppression

ABSTRACTTumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a novel transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway was sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

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Arkadia-SKI/SnoN signaling cascade differentially regulates TGF-β-induced iTreg and Th17 cell differentiation

10.1101/2021.02.23.432519 ◽

2021 ◽

Author(s):

Hao Xu ◽

Lin Wu ◽

Henry Nguyen ◽

Kailin R. Mesa ◽

Varsha Raghavan ◽

...

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Treg Cell ◽

T Cell Subsets ◽

Mucosal Inflammation ◽

Genetic Ablation ◽

Downstream Signaling ◽

Itreg Cell

AbstractTGF-β signaling is fundamental for both Th17 and regulatory T cell (Treg) differentiation. However, these cells differ in requirements for downstream signaling components, such as various SMAD effectors, for their differentiation. To further characterize the mechanisms that distinguish TGF-β signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), a RING type E3 ubiquitin ligase known to enhance TGF-β signaling during development. We find that Arkadia mediates the differentiation of induced-Treg (iTreg) but not Th17 cells both in vitro and in vivo. Inactivation of Arkadia in CD4+ T cells resulted in impairment of Treg cell differentiation in vitro and loss of RORγt+FOXP3+ iTreg cells in the intestinal lamina propria in vivo, which increased susceptibility to microbiota-induced mucosal inflammation. Furthermore, genetic ablation of two substrates of Arkadia, the transcriptional co-repressors SKI and SnoN, rescued in vitro and in vivo iTreg cell-differentiation of Arkadia-deficient cells. These results reveal distinct TGF-β signaling modules that govern Th17 and iTreg cell differentiation programs and that could be exploited therapeutically to selectively modulate T cell subsets in pathological settings such as autoimmunity or cancer.

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IMMU-11. DUAL TARGETING OF IL-6 AND CD40 OVERCOMES GLIOBLASTOMA RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE

Neuro-Oncology ◽

10.1093/neuonc/noaa215.442 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii107-ii107

Author(s):

Fan Yang ◽

Steven Brem ◽

Yi Fan

Keyword(s):

T Cell ◽

Immune Checkpoint Blockade ◽

Genetically Engineered ◽

Checkpoint Blockade ◽

Cell Infiltration ◽

Genetic Ablation ◽

T Cell Infiltration ◽

Dual Targeting ◽

Animal Survival ◽

Cd40 Expression

Abstract Glioblastoma (GBM) is refractory to current T cell-based immunotherapies such as checkpoint blockade. GBM is characterized by extensive infiltration of immunosuppressive macrophages (Mφs) that contribute to the treatment resistance. Here we develop a dual-targeting strategy to synergistically activate tumor-associated Mφs, which overcomes GBM resistance to therapeutic blockade of the PD1 and CTLA4 checkpoints. Consistent with a previously established role of IL-6 in alternative Mφ polarization, we show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T cell infiltration and enhances animal survival in a genetically engineered mouse GBM model. However, IL-6 inhibition does not synergize PD-1 and CTLA-4 blockade in GBM. Interestingly, we reveal that anti-IL-6 therapy reduces CD40 expression in GBM-associated Mφs. Our transcriptome analysis identifies a Stat3/HIF-1a-mediated axis, through which IL-6 regulates CD40 expression in Mφs. Finally, we show that combination of IL-6 blockade with CD40 stimulation robustly reverses Mφ-mediated tumor immunosuppression, enhances T cell infiltration, and sensitizes GBM to PD-1 and CTLA-4 blockade treatment, cumulating in inhibited tumor growth and extended animal survival. These findings illustrate a cellular mechanism that regulates Mφ-mediated tumor immunity, and suggest that dual-targeting IL-6 and CD40 may offer exciting opportunities for improving immunotherapy against GBM.

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CRIg, a tissue-resident macrophage specific immune checkpoint molecule, promotes immunological tolerance in NOD mice, via a dual role in effector and regulatory T cells

eLife ◽

10.7554/elife.29540 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 10

Author(s):

Xiaomei Yuan ◽

Bi-Huei Yang ◽

Yi Dong ◽

Asami Yamamura ◽

Wenxian Fu

Keyword(s):

T Cell ◽

T Cell Activation ◽

Immune Checkpoint ◽

Cell Activation ◽

Interleukin 2 ◽

Treg Cells ◽

Immunological Tolerance ◽

Dual Function ◽

Genetic Ablation ◽

Checkpoint Molecule

How tissue-resident macrophages (TRM) impact adaptive immune responses remains poorly understood. We report novel mechanisms by which TRMs regulate T cell activities at tissue sites. These mechanisms are mediated by the complement receptor of immunoglobulin family (CRIg). Using animal models for autoimmune type 1 diabetes (T1D), we found that CRIg+ TRMs formed a protective barrier surrounding pancreatic islets. Genetic ablation of CRIg exacerbated islet inflammation and local T cell activation. CRIg exhibited a dual function of attenuating early T cell activation and promoting the differentiation of Foxp3+ regulatory (Treg) cells. More importantly, CRIg stabilized the expression of Foxp3 in Treg cells, by enhancing their responsiveness to interleukin-2. The expression of CRIg in TRMs was postnatally regulated by gut microbial signals and metabolites. Thus, environmental cues instruct TRMs to express CRIg, which functions as an immune checkpoint molecule to regulate adaptive immunity and promote immune tolerance.

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