scholarly journals Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eric H. Bent ◽  
Luis R. Millán-Barea ◽  
Iris Zhuang ◽  
Daniel R. Goulet ◽  
Julia Fröse ◽  
...  
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Lymphoblastic Leukemia ◽  
Genotoxic Stress ◽  
Tumor Cell Apoptosis ◽  
Cell Clearance ◽  
Anti Cancer ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Deficient Mice

AbstractCytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cell death in vivo are currently unclear. Using a mouse model of BCR-ABL+ B-cell acute lymphoblastic leukemia, we show that chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of the cytokine IL-6. The chemotherapeutic doxorubicin is curative in IL-6-deficient mice through the induction of CD8+ T-cell-mediated anti-cancer responses, while moderately extending lifespan in wild type tumor-bearing mice. We also show that IL-6 suppresses the effectiveness of immune-checkpoint inhibition with anti-PD-L1 blockade. Our results suggest that IL-6 is a key regulator of anti-cancer immune responses induced by genotoxic stress and that its inhibition can switch cancer cell clearance from primarily apoptotic to immunogenic, promoting and maintaining durable anti-tumor immune responses.

Apurinic/Apyrimidinic Endonuclease 1 Induced Genomic Instability Causes T-Cell Acute Lymphoblastic Leukemia in Zebrafish

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1431-1431
Author(s):  
Jianhong Lin ◽  
Chun Yang ◽  
Ariel Kwart ◽  
Jianjun Zhao ◽  
Mehmet K Samur ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Transgenic Zebrafish ◽  
Advisory Committees ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Equity Ownership ◽  
Lymphoblastic Cells

Abstract Genomic instability is not only a hallmark of cancer, but potentially a primary mechanism for its occurrence. DNA repair mechanisms play a protective role during DNA damage induced by both normal metabolic activities and environmental factors such as reactive oxygen species (ROS), UV light and γ-irradiation. Genes related to DNA repair are usually considered as tumor suppressors. However, incomplete repair may induce severe genomic instability, leading eventually to transformation. Apurinic/apyrimidinic endonuclease 1 (APEX1), a gene involved in DNA repair with an important role in the base excision repair pathway, leads to transformation of normal cells in vitro. To investigate the role of APEX1 in tumor initiation in vivo, we generated a novel transgenic zebrafish model to overexpress APEX1 in fish. Specifically, pDestTol2A2_ubi:loxP-EGFP-loxP-APEX1-mCherry plasmid was injected into single cell embryos derived from the TP53 mutant line Tp53M214K/M214K to generate a stable conditional inducible transgenic zebrafish line: Tg:APEX1fl/- mCherry Tp53M214K/M214K. To activate APEX1 expression in vivo, this line was mated with Tg:HSP70-Cre+/+ fish. Compound zebrafish Tg: APEX1fl/- mCherry,Tp53+/M214K ,HSP70-Cre+/- carrying a Cre-activatable APEX1 knock-in allele were heated at 24hpf, and induction of APEX1 expression was monitored by downstream reporter - mCherry expression. Ten to twelve months post-fertilization, Tg:APEX1fl/- mCherry,Tp53+/M214K ,HSP70-Cre+/- fish developed abnormal swelling. Flow cytometry analysis of fish kidney marrow and peripheral blood showed dramatically increased precursor populations in scatter analysis. Histopathologic analysis showed that multiple organs were infiltrated with malignant lymphoblastic cells. None of the control fish Tg: GFP,Tp53+/M214K ,HSP70-Cre+/- developed tumors during their life span. Zebrafish with T-ALL have heterozygous Tp53+/M214K background, but the expression of p21, mdm2 and bax in Tp53+/M214K fish is exactly the same as in Tp53+/+ fish; and Tp53+/M214K zebrafish themselves have not developed tumors during their life span. RNA from lymphoblastic cells was evaluated by qRT-PCR and showed increased expression of CD3, LCK and Tal indicating a T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). We have performed whole genomic DNA sequencing in extracted DNA from fish tumor cells and compared it with their normal counterpart and observed multiple copy number changes and mutations. We have now begun to see the development of other tumors in other organs including the eye and the testis. To uncover the molecular mechanism of tumorigenesis induced by APEX1, we have performed Mass Spectrometry analysis on APEX1 pulled down from 293T and AG08498 cells ectopically expressing APEX1. Besides verified binding proteins, such as PCNA, we also identified Ku70 and Ku80 binding to APEX1 directly. Further immunoflurescent staining and confocal microscopy of 293T cells also found co-localization of APEX1 and Ku70/Ku80. Those two proteins initiate Non-Homologous End Joining (NHEJ) repair and start the error-prone double strand repair and DNA damage. These results indicate that excessive repair activity may induce DNA damage and genomic instability. In summary, this is the first demonstration where overexpression of a DNA repair gene is responsible for induction of genomic instability leading to malignant transformation. It provides new insight into the process of tumorigenesis and development of both therapy as well as preventive strategies. Disclosures Zon: FATE Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Scholar Rock: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder.

scholarly journals Research and Clinical Landscape of Bispecific Antibodies for the Treatment of Solid Malignancies

2021 ◽  
Vol 14 (9) ◽  
pp. 884
Author(s):  
Gabriele Antonarelli ◽  
Federica Giugliano ◽  
Chiara Corti ◽  
Matteo Repetto ◽  
Paolo Tarantino ◽  
...  
Keyword(s):  
Immune Responses ◽  
Solid Tumors ◽  
Lymphoblastic Leukemia ◽  
Target Selection ◽  
Therapy Resistance ◽  
Bispecific Antibodies ◽  
Fda Approval ◽  
Solid Malignancies ◽  
Anti Cancer ◽  
Cell Acute Lymphoblastic Leukemia

Solid tumors adopt multiple mechanisms to grow, evade immune responses, and to withstand therapeutic approaches. A major breakthrough in the armamentarium of anti-cancer agents has been the introduction of monoclonal antibodies (mAbs), able to inhibit aberrantly activated pathways and/or to unleash antigen (Ag)-specific immune responses. Nonetheless, mAb-mediated targeted pressure often fails due to escape mechanisms, mainly Ag loss/downregulation, ultimately providing therapy resistance. Hence, in order to target multiple Ag at the same time, and to facilitate cancer-immune cells interactions, bispecific antibodies (bsAbs) have been developed and are being tested in clinical trials, yielding variable safety/efficacy results based on target selection and their structure. While in hematologic cancers the bsAb blinatumomab recently reached the Food and Drug Administration (FDA)-approval for B Cell Acute Lymphoblastic Leukemia, bsAbs use in solid tumors faces considerable challenges, such as target Ag selection, biodistribution, and the presence of an immune-suppressive tumor microenvironment (TME). This review will focus on the state-of-the art, the design, and the exploitation of bsAbs against solid malignancies, delineating their mechanisms of action, major pitfalls, and future directions.

scholarly journals BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shuiyan Wu ◽  
You Jiang ◽  
Yi Hong ◽  
Xinran Chu ◽  
Zimu Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
Caspase 3 ◽  
Lymphoblastic Leukemia ◽  
Rna Seq ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Bet Protein

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

scholarly journals A Critical Role for Fas Ligand in the Active Suppression of Systemic Immune Responses by Ultraviolet Radiation

1999 ◽  
Vol 189 (8) ◽  
pp. 1285-1294 ◽  
Author(s):  
Laurie L. Hill ◽  
Vijay K. Shreedhar ◽  
Margaret L. Kripke ◽  
Laurie B. Owen-Schaub
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Immune Suppression ◽  
Fas Ligand ◽  
Critical Role ◽  
Cell Activity ◽  
Contact Hypersensitivity ◽  
Delayed Type Hypersensitivity ◽  
Intact Cells

Induction of antigen-specific suppression elicited by environmental insults, such as ultraviolet (UV)-B radiation in sunlight, can inhibit an effective immune response in vivo and may contribute to the outgrowth of UV-induced skin cancer. Although UV-induced DNA damage is known to be an initiating event in the immune suppression of most antigen responses, the underlying mechanism(s) of such suppression remain undefined. In this report, we document that Fas ligand (FasL) is critical for UV-induced systemic immune suppression. Normal mice acutely exposed to UV exhibit a profound suppression of both contact hypersensitivity and delayed type hypersensitivity (DTH) reactions and the development of transferable antigen-specific suppressor cells. FasL-deficient mice exposed to UV lack both transferable suppressor cell activity and primary suppression to all antigens tested, with the exception of the DTH response to allogeneic spleen cells. Interestingly, suppression of this response is also known to occur independently of UV-induced DNA damage. Delivery of alloantigen as protein, rather than intact cells, restored the requirement for FasL in UV-induced immune suppression of this response. These results substantiate that FasL/Fas interactions are essential for systemic UV-induced suppression of immune responses that involve host antigen presentation and suggest an interrelationship between UV-induced DNA damage and FasL in this phenomenon. Collectively, our results suggest a model whereby UV-induced DNA damage disarms the immune system in a manner similar to that observed in immunologically privileged sites.

scholarly journals V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites⋆

2002 ◽  
Vol 195 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Rodrig Marculescu ◽  
Trang Le ◽  
Paul Simon ◽  
Ulrich Jaeger ◽  
Bertrand Nadel
Keyword(s):  
T Cell ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Lymphoid Malignancies ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Normal Human ◽  
Hodgkin's Lymphomas ◽  
The Impact

Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin’s lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.

scholarly journals The research significance of concomitant use of CAR-CD138-NK and CAR-CD19-NK to target multiple myelomas

2018 ◽  
Vol 16 ◽  
pp. 205873921878896 ◽  
Author(s):  
Songbo Zhao ◽  
Zhichao Han ◽  
Cheng Ji ◽  
Gangli An ◽  
Huimin Meng ◽  
...  
Keyword(s):  
Nk Cells ◽  
Lymphoblastic Leukemia ◽  
Small Subset ◽  
Novel Drugs ◽  
Prevalent Disease ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Multiple Myelomas ◽  
Made In

Multiple myeloma (MM) is a type of cancer characterized by abnormal proliferation of clonal cells; it is the very dangerous and highly prevalent disease. Although significant progress has been made in clinical research, especially with novel drugs such as bortezomib, lenalidomide, and carfilzomib, most of the patients with MM still suffer from often fetal relapses due to drug resistance. In this study, we aimed to develop immune cells that could specifically target and destroy MM cells. Chimeric antigen receptor–modified NK-92 (CAR-NK92) cells have been very effective against B-cell acute lymphoblastic leukemia (B-ALL); as MM shows high expression of CD138, we constructed CD138-directed CAR-NK-92MI cells (CAR-CD138). It 2is reported that there is a small subset of CD138–/CD19+ MM cells showing, to some extent, stem cell qualities. We therefore generated the CD19-directed CAR-NK-92MI cells (CAR-CD19) as well. These two CAR-NK cells showed strong in vitro biological activity in specifically killing target tumor cells. Thus, the concomitant use of these CAR-NK cells may achieve excellent results in vivo.

scholarly journals Inducible transgene expression in PDX models in vivo identifies KLF4 as therapeutic target for B-ALL

2019 ◽  
Author(s):  
Wen-Hsin Liu ◽  
Paulina Mrozek-Gorska ◽  
Tobias Herold ◽  
Larissa Schwarzkopf ◽  
Dagmar Pich ◽  
...  
Keyword(s):  
Residual Disease ◽  
Therapeutic Option ◽  
Lymphoblastic Leukemia ◽  
Clinical Model ◽  
Novel Technique ◽  
Pdx Model ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Disease Stages ◽  
Pdx Models

Clinic-close methods are not available that prioritize and validate potential therapeutic targets in individual tumors from the vast bulk of descriptive expression data. We developed a novel technique to express transgenes in established patient-derived xenograft (PDX) models in vivo to fill this gap. With this technique at hand, we analyzed the role of transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive pre-clinical in vivo trials, we found that re-expression of wild type KLF4 reduced leukemia load in PDX models of B-ALL, with strongest effects after conventional chemotherapy at minimal residual disease (MRD). A non-functional KLF4 mutant had no effect in this model. Re-expressing KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. Of major translational relevance, Azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced Azacitidine-induced cell death, suggesting that Azacitidine can regulate KLF4 re-expression. These results support applying Azacitidine in patients with B-ALL to regulated KLF4 as a therapeutic option. Taken together, our novel technique allows studying the function of dysregulated genes in a highly clinic-related, translational context and testing clinically applicable drugs in a relevant pre-clinical model.

scholarly journals STAT2-Dependent Immune Responses Ensure Host Survival despite the Presence of a Potent Viral Antagonist

2018 ◽  
Vol 92 (14) ◽  
Author(s):  
Vu Thuy Khanh Le-Trilling ◽  
Kerstin Wohlgemuth ◽  
Meike U. Rückborn ◽  
Andreja Jagnjic ◽  
Fabienne Maaßen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Mutual Influence ◽  
Type I ◽  
Mcmv Infection ◽  
General Importance ◽  
Interferon Antagonism ◽  
Deficient Mice

ABSTRACTA pathogen encounter induces interferons, which signal via Janus kinases and STAT transcription factors to establish an antiviral state. However, the host and pathogens are situated in a continuous arms race which shapes host evolution toward optimized immune responses and the pathogens toward enhanced immune-evasive properties. Mouse cytomegalovirus (MCMV) counteracts interferon responses by pM27-mediated degradation of STAT2, which directly affects the signaling of type I as well as type III interferons. Using MCMV mutants lackingM27and mice lacking STAT2, we studied the opposing relationship between antiviral activities and viral antagonism in a natural host-pathogen pairin vitroandin vivo. In contrast to wild-type (wt) MCMV, ΔM27 mutant MCMV was efficiently cleared from all organs within a few days in BALB/c, C57BL/6, and 129 mice, highlighting the general importance of STAT2 antagonism for MCMV replication. Despite this effective and relevant STAT2 antagonism, wt and STAT2-deficient mice exhibited fundamentally different susceptibilities to MCMV infections. MCMV replication was increased in all assessed organs (e.g., liver, spleen, lungs, and salivary glands) of STAT2-deficient mice, resulting in mortality during the first week after infection. Taken together, the results of our study reveal the importance of cytomegaloviral interferon antagonism for viral replication as well as a pivotal role of the remaining STAT2 activity for host survival. This mutual influence establishes a stable evolutionary standoff situation with fatal consequences when the equilibrium is disturbed.IMPORTANCEThe host limits viral replication by the use of interferons (IFNs), which signal via STAT proteins. Several viruses evolved antagonists targeting STATs to antagonize IFNs (e.g., cytomegaloviruses, Zika virus, dengue virus, and several paramyxoviruses). We analyzed infections caused by MCMV expressing or lacking the STAT2 antagonist pM27 in STAT2-deficient and control mice to evaluate its importance for the host and the virusin vitroandin vivo. The inability to counteract STAT2 directly translates into exaggerated IFN susceptibilityin vitroand pronounced attenuationin vivo. Thus, the antiviral activity mediated by IFNs via STAT2-dependent signaling drove the development of a potent MCMV-encoded STAT2 antagonist which became indispensable for efficient virus replication and spread to organs required for dissemination. Despite this clear impact of viral STAT2 antagonism, the host critically required the remaining STAT2 activity to prevent overt disease and mortality upon MCMV infection. Our findings highlight a remarkably delicate balance between host and virus.

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