scholarly journals TNFa and IL2 Encoding Oncolytic Adenovirus Activates Pathogen and Danger-Associated Immunological Signaling

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 798 ◽  
Author(s):  
Camilla Heiniö ◽  
Riikka Havunen ◽  
Joao Santos ◽  
Klaas de Lint ◽  
Victor Cervera-Carrascon ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Oncolytic Adenovirus ◽  
Adenovirus Infection ◽  
Tumor Resistance ◽  
Antitumor Response ◽  
Specific Effects ◽  
Molecular Pattern ◽  
Pathogen Associated Molecular Pattern

In order to break tumor resistance towards traditional treatments, we investigate the response of tumor and immune cells to a novel, cytokine-armed oncolytic adenovirus: Ad5/3-d24-E2F-hTNFa-IRES-hIL2 (also known as TILT-123 and OAd.TNFa-IL2). There are several pattern recognition receptors (PRR) that might mediate adenovirus-infection recognition. However, the role and specific effects of each PRR on the tumor microenvironment and treatment outcome remain unclear. Hence, the aim of this study was to investigate the effects of OAd.TNFa-IL2 infection on PRR-mediated danger- and pathogen-associated molecular pattern (DAMP and PAMP, respectively) signaling. In addition, we wanted to see which PRRs mediate an antitumor response and are therefore relevant for optimizing this virotherapy. We determined that OAd.TNFa-IL2 induced DAMP and PAMP release and consequent tumor microenvironment modulation. We show that the AIM2 inflammasome is activated during OAd.TNFa-IL2 virotherapy, thus creating an immunostimulatory antitumor microenvironment.

scholarly journals Interactions between tumor-derived proteins and Toll-like receptors

2020 ◽  
Vol 52 (12) ◽  
pp. 1926-1935
Author(s):  
Gun-Young Jang ◽  
Ji won Lee ◽  
Young Seob Kim ◽  
Sung Eun Lee ◽  
Hee Dong Han ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Tissue Injury ◽  
Suppressor Cells ◽  
Toll Like Receptors ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Dying Cells

AbstractDamage-associated molecular patterns (DAMPs) are danger signals (or alarmins) alerting immune cells through pattern recognition receptors (PRRs) to begin defense activity. Moreover, DAMPs are host biomolecules that can initiate a noninflammatory response to infection, and pathogen-associated molecular pattern (PAMPs) perpetuate the inflammatory response to infection. Many DAMPs are proteins that have defined intracellular functions and are released from dying cells after tissue injury or chemo-/radiotherapy. In the tumor microenvironment, DAMPs can be ligands for Toll-like receptors (TLRs) expressed on immune cells and induce cytokine production and T-cell activation. Moreover, DAMPs released from tumor cells can directly activate tumor-expressed TLRs that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Therefore, regulation of DAMP proteins can reduce excessive inflammation to create an immunogenic tumor microenvironment. Here, we review tumor-derived DAMP proteins as ligands of TLRs and discuss their association with immune cells, tumors, and the composition of the tumor microenvironment.

scholarly journals Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity

2021 ◽  
Vol 9 (1) ◽  
pp. e001595
Author(s):  
Xiaofei Yu ◽  
Wenjie Liu ◽  
Shixian Chen ◽  
Xueqian Cheng ◽  
Patrick A Paez ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Tumor Microenvironment ◽  
Antitumor Immunity ◽  
Pattern Recognition Receptor ◽  
Immunostimulatory Activity ◽  
Immunological Mechanism ◽  
Molecular Pattern ◽  
Immunosuppressive Tumor Microenvironment ◽  
Toll Like Receptor 5 ◽  
Recognition Receptor

BackgroundThe efficacy of cancer immunotherapy can be limited by the poor immunogenicity of cancer and the immunosuppressive tumor microenvironment (TME). Immunologically programming the TME and creating an immune-inflamed tumor phenotype is critical for improving the immune-responsiveness of cancers. Here, we interrogate the immune modulator Flagrp170, engineered via incorporation of a pathogen-associated molecular pattern (ie, flagellin) into an immunostimulatory chaperone molecule, in transforming poorly immunogenic tumors and establishing a highly immunostimulatory milieu for immune augmentation.MethodsMultiple murine cancer models were used to evaluate the immunostimulatory activity, antitumor potency, and potential side effects of Flagrp170 on administration into the tumors using a replication impaired adenovirus. Antibody neutralization and mice deficient in pattern recognition receptors, that is, toll-like receptor 5 (TLR5) and NOD like receptor (NLR) family caspase activation and recruitment domain (CARD) domain-containing protein 4 (NLRC4), both of which can recognize flagellin, were employed to understand the immunological mechanism of action of the Flagrp170.ResultsIntratumoral delivery of mouse or human version of Flagrp170 resulted in robust inhibition of multiple malignancies including head and neck squamous cell carcinoma and breast cancer, without tissue toxicities. This in situ Flagrp170 treatment induced a set of cytokines in the TME known to support Th1/Tc1-dominant antitumor immunity. Additionally, granulocyte macrophage colony-stimulating factor derived from mobilized CD8+ T cells was involved in the therapeutic activity of Flagrp170. We also made a striking finding that NLRC4, not TLR5, is required for Flagrp170-mediated antitumor immune responses.ConclusionOur results elucidate a novel immune-potentiating activity of Flagrp170 via engaging the innate pattern recognition receptor NLRC4, and support its potential clinical use to reshape cancer immune phenotype for overcoming therapeutic resistance.

scholarly journals Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Michaël Cerezo ◽  
Stéphane Rocchi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Metabolic Pathways ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Limited Resources ◽  
Antitumor Response ◽  
Secondary Resistance

Abstract By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.

scholarly journals Systemic oncolytic adenovirus delivered in mesenchymal carrier cells modulate tumor infiltrating immune cells and tumor microenvironment in mice with neuroblastoma

Oncotarget ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 347-361 ◽  
Author(s):  
Lidia Franco-Luzón ◽  
África González-Murillo ◽  
Cristina Alcántara-Sánchez ◽  
Lorena García-García ◽  
Maryam Tabasi ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Oncolytic Adenovirus
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