scholarly journals The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2470
Author(s):  
Athanasios G. Papavassiliou ◽  
Anna Maria Musti
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Biological Activity ◽  
Transcription Factors ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Acute Infection ◽  
Regulation Of Gene Expression ◽  
Basic Leucine Zipper

c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types. In particular, we focus on the current understanding of the role of c-Jun/AP-1 in the response of CD8 T cells to acute infection and cancer. We highlight the transcriptional and epigenetic regulatory mechanisms through which c-Jun/AP-1 participates in the productive immune response of CD8 T cells, and how its downregulation may contribute to the dysfunctional state of tumor infiltrating CD8 T cells. Additionally, we discuss recent insights pointing at c-Jun as a suitable target for immunotherapy-based combination approaches to reinvigorate anti-tumor immune functions.

scholarly journals Hdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Rong En Tay ◽  
Olamide Olawoyin ◽  
Paloma Cejas ◽  
Yingtian Xie ◽  
Clifford A. Meyer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Transcriptional Control ◽  
Cell Activation ◽  
Acute Infection ◽  
Cd8 T Cell ◽  
Cell Cytotoxicity ◽  
T Cell Cytotoxicity

Cytotoxic T cells play a key role in adaptive immunity by killing infected or cancerous cells. While the transcriptional control of CD8 T cell differentiation and effector function following T cell activation has been extensively studied, little is known about epigenetic regulation of these processes. Here we show that the histone deacetylase HDAC3 inhibits CD8 T cell cytotoxicity early during activation and is required for persistence of activated CD8 T cells following resolution of an acute infection. Mechanistically, HDAC3 inhibits gene programs associated with cytotoxicity and effector differentiation of CD8 T cells including genes encoding essential cytotoxicity proteins and key transcription factors. These data identify HDAC3 as an epigenetic regulator of the CD8 T cell cytotoxicity program.

scholarly journals Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

1997 ◽  
Vol 17 (11) ◽  
pp. 6437-6447 ◽  
Author(s):  
S Martínez-Martínez ◽  
P Gómez del Arco ◽  
A L Armesilla ◽  
J Aramburu ◽  
C Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Regulation Of Gene Expression ◽  
Interleukin 2 ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Nf Kappab

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants.

scholarly journals Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

2021 ◽  
Vol 6 (57) ◽  
pp. eabf7570
Author(s):  
Laura A. Vella ◽  
Josephine R. Giles ◽  
Amy E. Baxter ◽  
Derek A. Oldridge ◽  
Caroline Diorio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Vascular Complications ◽  
Adult Disease ◽  
Vasoactive Medication ◽  
Inflammatory Syndrome

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

scholarly journals EXTH-43. GENERATION OF A B-CELL-BASED VACCINE FOR THE TREATMENT OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii96-ii96
Author(s):  
Catalina Lee Chang ◽  
Jason Miska ◽  
David Hou ◽  
Aida Rashidi ◽  
Peng Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cross Presentation ◽  
Control Tumor Growth ◽  
Efficient Alternative ◽  
Control Tumor ◽  
Secondary Lymphoid Organs

Abstract Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNg stimulation. BVaxmigrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunologic memory that prevented the growth of new tumors upon subsequent re-injection in cured mice. GBM patient-derived BVax were successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. In addition to the role in activating CD8+ T cells, BVax produce tumor-specific antibodies able to control tumor growth via antibody-mediated cell cytotoxicity. In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

scholarly journals Selective Bystander Proliferation of Memory CD4+ and CD8+ T Cells Upon NK T or T Cell Activation

2000 ◽  
Vol 165 (8) ◽  
pp. 4305-4311 ◽  
Author(s):  
Gérard Eberl ◽  
Pierre Brawand ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation

scholarly journals Antitumor effect of Batf2 through IL-12 p40 up-regulation in tumor-associated macrophages

2017 ◽  
Vol 114 (35) ◽  
pp. E7331-E7340 ◽  
Author(s):  
Hisashi Kanemaru ◽  
Fumihiro Yamane ◽  
Kiyoharu Fukushima ◽  
Takanori Matsuki ◽  
Takahiro Kawasaki ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Progression ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antitumor Effect ◽  
Leucine Zipper ◽  
Cancer Prognosis ◽  
Tumor Associated Macrophages ◽  
Basic Leucine Zipper

The development of effective treatments against cancers is urgently needed, and the accumulation of CD8+ T cells within tumors is especially important for cancer prognosis. Although their mechanisms are still largely unknown, growing evidence has indicated that innate immune cells have important effects on cancer progression through the production of various cytokines. Here, we found that basic leucine zipper transcription factor ATF-like 2 (Batf2) has an antitumor effect. An s.c. inoculated tumor model produced fewer IL-12 p40+ macrophages and activated CD8+ T cells within the tumors of Batf2−/− mice compared with WT mice. In vitro studies also revealed that the IL-12 p40 expression was significantly lower in Batf2−/− macrophages following their stimulation by toll-like receptor ligands, such as R848. Additionally, we found that BATF2 interacts with p50/p65 and promotes IL-12 p40 expression. In conclusion, Batf2 has an antitumor effect through the up-regulation of IL-12 p40 in tumor-associated macrophages, which eventually induces CD8+ T-cell activation and accumulation within the tumor.

A Randomized Phase II Trial of Idiotype Vaccination and Adoptive Autologous T-Cell Transfer in Multiple Myeloma patients

Blood ◽  
2021 ◽  
Author(s):  
Muzaffar H Qazilbash ◽  
Neeraj Y Saini ◽  
Cha Soung-chul ◽  
Zhe Wang ◽  
Edward Stadtmauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase Ii ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Phase Ii Trial ◽  
Ex Vivo ◽  
Vaccine Strategy ◽  
Randomized Phase Ii

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding anti-myeloma idiotype-keyhole limpet hemocyanin (Id-KLH) vaccine to vaccine-specific co-stimulated T cells. In this randomized, phase II trial, eligible patients received either the control (KLH only) or Id-KLH vaccine, an auto-transplant, vaccine-specific co-stimulated T-cells expanded ex-vivo, and two booster doses of the assigned vaccine. In 36 patients (20 in KLH, 16 in Id-KLH) enrolled, no dose-limiting toxicity was seen in either arm. At last evaluation, 6 (30%) and 8 (50%) had achieved complete remission in KLH-only and Id-KLH, respectively (p=0.22) and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; p=0.32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with KLH-only patients, there was a greater change in IR genes in T-cells in Id-KLH patients relative to baseline. Specifically, upregulation of genes associated with activation, induction of effector function, and generation of memory CD8+ T cells after Id-KLH, but not after KLH control vaccination, was observed. Similarly, responding patients across both arms were associated with upregulation of genes associated with T-cell activation. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of Id-KLH patients analyzed. In conclusion, in this combination immunotherapy approach, we observed a significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies.

scholarly journals Activation Outcomes Induced in Naïve CD8 T-Cells by Macrophages Primed via “Phagocytic” and Nonphagocytic Pathways

2008 ◽  
Vol 19 (2) ◽  
pp. 701-710 ◽  
Author(s):  
Isabel María Olazabal ◽  
Noa Beatriz Martín-Cofreces ◽  
María Mittelbrunn ◽  
Gloria Martínez del Hoyo ◽  
Balbino Alarcón ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
Microtubule Organizing Center ◽  
Antigen Uptake ◽  
Soluble Peptide

The array of phagocytic receptors expressed by macrophages make them very efficient at pathogen clearance, and the phagocytic process links innate with adaptive immunity. Primary macrophages modulate antigen cross-presentation and T-cell activation. We assessed ex vivo the putative role of different phagocytic receptors in immune synapse formation with CD8 naïve T-cells from OT-I transgenic mice and compared this with the administration of antigen as a soluble peptide. Macrophages that have phagocytosed antigen induce T-cell microtubule-organizing center and F-actin cytoskeleton relocalization to the contact site, as well as the recruitment of proximal T-cell receptor signals such as activated Vav1 and PKCθ. At the same doses of loaded antigen (1 μM), “phagocytic” macrophages were more efficient than peptide-antigen–loaded macrophages at forming productive immune synapses with T-cells, as indicated by active T-cell TCR/CD3 conformation, LAT phosphorylation, IL-2 production, and T-cell proliferation. Similar T-cell proliferation efficiency was obtained when low doses of soluble peptide (3–30 nM) were loaded on macrophages. These results suggest that the pathway used for antigen uptake may modulate the antigen density presented on MHC-I, resulting in different signals induced in naïve CD8 T-cells, leading either to CD8 T-cell activation or anergy.

scholarly journals 702 TJ-CD4B (ABL111), a Claudin18.2-targeted 4-1BB tumor engager induces potent tumor-dependent immune response without dose-limiting toxicity in preclinical studies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A730-A730
Author(s):  
Wenqing Jiang ◽  
Zhengyi Wang ◽  
Zhen Sheng ◽  
Jaeho Jung ◽  
Taylor Guo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Gene Expression Analysis ◽  
Cell Activation ◽  
Clinical Development ◽  
Cynomolgus Monkeys ◽  
Anti Tumor Activity

Background4-1BB (CD137) is a co-stimulatory receptor that stimulates the function of multiple immune cells. Its ability to induce potent anti-tumor activity makes 4-1BB an attractive target for immuno-oncology. However, clinical development of a monospecific 4-1BB agonistic antibody has been hampered by dose-limiting hepatic toxicities. To minimize systemic toxicities, we have developed a novel Claudin18.2 (CLDN18.2) x 4-1BB bispecific antibody, TJ-CD4B (ABL111) that stimulates 4-1BB pathway only when it engages with Claudin 18.2, a tumor-associated antigen specifically expressed in gastrointestinal cancers. TJ-CD4B (ABL111) is now being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT04900818).MethodsTJ-CD4B (ABL111) was evaluated in vivo using the human 4-1BB knock-in mice bearing CLDN18.2 expressing MC38 tumor cells. Pharmacodynamic effects upon treatment were characterized in tumor tissue and blood. Immunophenotyping of the tumor microenvironment (TME) and peripheral blood was performed by flow cytometry. Soluble biomarkers were measured using Luminex-based multiplex assay. In-depth gene expression analysis was performed on primary human CD8+ T cells that were co-cultured with CLDN18.2 expressing cells in the presence of anti-CD3 using NanoString nCounter®. Pharmacokinetic (PK) and toxicity study were performed in cynomolgus monkeys.ResultsTJ-CD4B (ABL111) elicited complete tumor regression in 13 out of 18 MC38 tumor bearing mice given at a dose above 2 mg/kg. Dose-dependent anti-tumor activity was associated with enhanced T cell activation in TME and expansion of memory T cells in the peripheral blood. Increased CD8+ T cells number and proliferation were observed in both tumor nest and surrounding stroma while the level of soluble 4-1BB in the serum was also elevated in response to the treatment. In vitro gene expression analysis by Nanostring revealed TJ-CD4B(ABL111) effectively activated immune pathways characterized by IFN?-signaling and T cell inflammation. Preclinically, TJ-CD4B was well tolerated at the repeated doses up to 100 mg/kg/wk in cynomolgus monkeys without the adverse influence on the liver function which is generally affected by 4-1BB activation. Besides, no cytokine release or immune activation was observed in the periphery.ConclusionsTJ-CD4B (ABL111) is a novel CLDN18.2 dependent 4-1BB bispecific agonist antibody that induced T cell activation and memory response in tumor with CLDN18.2 expression, leading to a strong anti-tumor activity in vivo. TJ-CD4B did not induce systemic immune response nor hepatic toxicity due to the CLDN18.2 dependent 4-1BB stimulation. These data warrant the current clinical development in phase I trial to validate the safety properties and tumor specific responses.

scholarly journals 368 Consistent pattern of immune activation induced by oncolytic adenovirus ONCOS-102 across diverse types of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A396-A396
Author(s):  
Lukasz Kuryk ◽  
Anne-Sophie Moller ◽  
Sandeep Kumar ◽  
Alexander Shoushtari ◽  
Luis Paz Ares ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Clinical Importance ◽  
Oncolytic Adenovirus ◽  
Link Type ◽  
Tumor Types

BackgroundSolid tumors exhibit highly variable compositions of immune infiltrates. Therapeutic compounds driving uniform remodeling of tumor microenvironment (TME) across tumor types may improve the efficacy of cancer immunotherapy. ONCOS-102, a granulocyte-macrophage colony stimulating factor (GM-CSF)-expressing oncolytic adenovirus (Ad5/3-D24-GMCSF), was tested for its safety, therapeutic efficacy and capacity to remodel TME in recently completed phase I/II clinical studies in anti-PD-1 refractory melanoma (NCT03003676) and malignant pleural mesothelioma (MPM) (NCT02879669).MethodsBiopsies were obtained from tumor lesions of patients treated with intra-tumoral injections of ONCOS-102 in combination with chemotherapy or pembrolizumab for MPM and melanoma, respectively. Tumor immune infiltrates were analyzed by immunohistology using several antibody panels. On-treatment biopsies were compared to paired baseline samples as wells as to samples from control patients treated with chemotherapy alone in the case of MPM. Gene expression data obtained by next generation RNA sequencing were used to complement the immunohistology analysis and all results were correlated to clinical outcomes.ResultsComparative TME analysis of anti-PD-1 refractory melanoma and MPM tumors revealed noticeably lower baseline T-cell infiltration in mesothelioma. Thus, fractions of CD8+ T-cells were significantly below 10% in 80% of MPM biopsies while approaching or exceeding this level in 60% of melanoma baseline samples. Comparison of tumor biopsies obtained at baseline or on-treatment, demonstrated increased infiltration by both CD4+ and CD8+ T-cells in large proportions of melanoma (CD4+: 13/20 (65%); CD8+: 16/19 (84%) and MPM (CD4+: 10/15 (67%); CD8+: 9/15 (60%) tumor lesions in response to ONCOS-102. Frequencies of cytotoxic T-cells with high granzyme-B expression also increased in response to the treatment in both tumor types, in particular when assessed as percentage of total CD8+ T-cells. Other observed changes induced by ONCOS-102 in samples taken from CR, PR and SD patients with MPM or melanoma included increased CD8/Treg ratio and modulation of PD-L1 expression. Biological and clinical importance of these findings was further supported by correlation between modulation of several subsets of genes related to the process of T-cell activation, such as cytotoxic granule components and co-stimulatory molecules, and clinical response to ONCOS-102 in melanoma and both tumor response and overall survival in MPM patients.ConclusionsONCOS-102 drives pro-inflammatory modulation of immune TME across tumor types of different origins, anatomical locations and immunological baseline characteristics. Our data support potential of ONCOS-102 to serve as a potent immune sensitizing agent in combination therapies with various classes of immunomodulatory compounds and chemotherapy.

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