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IFN-?: A New Inducer of Local Immunity against Cancer and Infections.

ABSTRACT: IFN-? is the newly established type III IFN with unique immunomodulatory functions. In contrast to the IFN-?/? family and to some extent IFN-?, IFN-? is apparently acting in specific areas of the body to activate resident immune cells and induces a local immunity, instrumental in preventing particular infections and also keeping transformed cells under control. Mucosal areas of lung and gastrointestinal tracts are now under scrutiny to elucidate the immune mechanisms triggered by IFN-? and leading to viral protection. New evidence also indicates the crucial role of IFN-? in promoting innate immunity in solid cancer models. Based on its unique biological activities among the IFN system, new immunotherapeutic approaches are now emerging for the treatment of cancer, infection, and autoimmune diseases. In the present review, we highlight the recent advances of IFN-? immunomodulatory functions. We also discuss the perspectives of IFN-? as a therapeutic agent.

SUBMITTER: Lasfar A

PROVIDER: S-EPMC5156659 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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IFN-λ: A New Inducer of Local Immunity against Cancer and Infections.

Lasfar Ahmed A Zloza Andrew A de la Torre Andrew A Cohen-Solal Karine A KA

Frontiers in immunology 20161215

IFN-λ is the newly established type III IFN with unique immunomodulatory functions. In contrast to the IFN-α/β family and to some extent IFN-γ, IFN-λ is apparently acting in specific areas of the body to activate resident immune cells and induces a local immunity, instrumental in preventing particular infections and also keeping transformed cells under control. Mucosal areas of lung and gastrointestinal tracts are now under scrutiny to elucidate the immune mechanisms triggered by IFN-λ and leadi ...[more]

PMID: 28018361

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Pulmonary-Resident Memory Lymphocytes: Pivotal Orchestrators of Local Immunity Against Respiratory Infections.

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| S-EPMC8485048 | biostudies-literature

Concerted action of IFN-α and IFN-λ induces local NK cell immunity and halts cancer growth.

Project description:Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. No significant improvement has been reported with currently available systemic therapies. IFN-α has been tested in both clinic and animal models and only moderate benefits have been observed. In animal models, similar modest antitumor efficacy has also been reported for IFN-λ, a new type of IFN that acts through its own receptor complex. In the present study, the antitumor efficacy of the combination of IFN-α and IFN-λ was tested in the BNL mouse hepatoma model. This study was accomplished by using either engineered tumor cells (IFN-α/IFN-λ gene therapy) or by directly injecting tumor-bearing mice with IFN-α/IFN-λ. Both approaches demonstrated that IFN-α/IFN-λ combination therapy was more efficacious than IFN monotherapy based on either IFN-α or IFN-λ. In complement to tumor surgery, IFN-α/IFN-λ combination induced complete tumor remission. Highest antitumor efficacy has been obtained following local administration of IFN-α/IFN-λ combination at the tumor site that was associated with strong NK cells tumor infiltration. This supports the use of IFN-α/IFN-λ combination as a new cancer immunotherapy for stimulating antitumor response after cancer surgery.

| S-EPMC5226505 | biostudies-literature

Genes conferring immunity against viral infections

Project description:Immunity against viral infection is different from that for other infections. The virus utilizes the host’s immune mechanism for its survival and infection. Innate immune reaction is initially activated by conserved pathogen-associated molecular patterns, pattern recognition receptors, retinoic acid-inducible gene I, MDA5, LGP2, and toll-like receptors (TLRs) such as TLR3 and TLR7. Some important molecules responsible for viral infection include cytokines and chemokines. The current chapter includes the basic mechanism of action of immune-response genes and a list of important genes and their protein IDs. Chemokines include CCL19 and CCL21, and reactivate antiviral CCR7, monocyte chemoattractant protein 1, a CC chemokine, and interleukin 8, an interferon-stimulated gene.

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Harnessing Type I IFN Immunity Against SARS-CoV-2 with Early Administration of IFN-β.

Project description: Not available

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IFN? is Required for Optimal Antibody-Mediated Immunity against Genital Chlamydia Infection.

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| S-EPMC5067755 | biostudies-literature

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Trained Immunity Confers Broad-Spectrum Protection Against Bacterial Infections.

Project description:BackgroundThe innate immune system recalls a challenge to adapt to a secondary challenge, a phenomenon called trained immunity. Training involves cellular metabolic, epigenetic and functional reprogramming, but how broadly trained immunity protects from infections is unknown. For the first time, we addressed whether trained immunity provides protection in a large panel of preclinical models of infections.MethodsMice were trained and subjected to systemic infections, peritonitis, enteritis, and pneumonia induced by Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, Citrobacter rodentium, and Pseudomonas aeruginosa. Bacteria, cytokines, leukocytes, and hematopoietic precursors were quantified in blood, bone marrow, and organs. The role of monocytes/macrophages, granulocytes, and interleukin 1 signaling was investigated using depletion or blocking approaches.ResultsInduction of trained immunity protected mice in all preclinical models, including when training and infection were initiated in distant organs. Trained immunity increased bone marrow hematopoietic progenitors, blood Ly6Chigh inflammatory monocytes and granulocytes, and sustained blood antimicrobial responses. Monocytes/macrophages and interleukin 1 signaling were required to protect trained mice from listeriosis. Trained mice were efficiently protected from peritonitis and listeriosis for up to 5 weeks.ConclusionsTrained immunity confers broad-spectrum protection against lethal bacterial infections. These observations support the development of trained immunity-based strategies to improve host defenses.

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HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma induced apoptosis

Project description:The success of cancer immunotherapy is limited to a subset of patients, highlighting the need to identify the processes by which tumors evade immunity. Using CRISPR/Cas9 screening, we reveal that melanoma cells lacking HOIP, the catalytic subunit of LUBAC, are highly susceptible to both NK and CD8+ T cell-mediated killing. We demonstrate that HOIP-deficient tumor cells exhibit increased sensitivity to the combined effect of the inflammatory cytokines, TNF and IFN-γ, released by NK and CD8+ T cells upon target recognition. Both genetic deletion and pharmacological inhibition of HOIP augments tumor cell sensitivity to combined TNF and IFN-γ. Together, we unveil a protective regulatory axis, involving HOIP, which limits a transcription-dependent form of cell death that engages both intrinsic and extrinsic apoptotic machinery upon exposure to TNF and IFN-γ. Our findings highlight HOIP inhibition as a potential strategy to harness and enhance the killing capacity of TNF and IFN-γ during immunotherapy.

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Harnessing anti-cytomegalovirus immunity for local immunotherapy against solid tumors.

Project description:Tumor infiltration by T cells profoundly affects cancer progression and responses to immunotherapy. However, the tumor immunosuppressive microenvironment can impair the induction, trafficking, and local activity of antitumor T cells. Here, we investigated whether intratumoral injection of virus-derived peptide epitopes could activate preexisting antiviral T cell responses locally and promote antitumor responses or antigen spreading. We focused on a mouse model of cytomegalovirus (CMV), a highly prevalent human infection that induces vigorous and durable T cell responses. Mice persistently infected with murine CMV (MCMV) were challenged with lung (TC-1), colon (MC-38), or melanoma (B16-F10) tumor cells. Intratumoral injection of MCMV-derived T cell epitopes triggered in situ and systemic expansion of their cognate, MCMV-specific CD4+ or CD8+ T cells. The MCMV CD8+ T cell epitopes injected alone provoked arrest of tumor growth and some durable remissions. Intratumoral injection of MCMV CD4+ T cell epitopes with polyinosinic acid:polycytidylic acid (pI:C) preferentially elicited tumor antigen-specific CD8+ T cells, promoted tumor clearance, and conferred long-term protection against tumor rechallenge. Notably, secondary proliferation of MCMV-specific CD8+ T cells correlated with better tumor control. Importantly, intratumoral injection of MCMV-derived CD8+ T cell-peptide epitopes alone or CD4+ T cell-peptide epitopes with pI:C induced potent adaptive and innate immune activation of the tumor microenvironment. Thus, CMV-derived peptide epitopes, delivered intratumorally, act as cytotoxic and immunotherapeutic agents to promote immediate tumor control and long-term antitumor immunity that could be used as a stand-alone therapy. The tumor antigen-agnostic nature of this approach makes it applicable across a broad range of solid tumors regardless of their origin.

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Murine and bovine ?? T cells enhance innate immunity against Brucella abortus infections.

Project description:?? T cells have been postulated to act as a first line of defense against infectious agents, particularly intracellular pathogens, representing an important link between the innate and adaptive immune responses. Human ?? T cells expand in the blood of brucellosis patients and are active against Brucella in vitro. However, the role of ?? T cells in vivo during experimental brucellosis has not been studied. Here we report TCR?(-/-) mice are more susceptible to B. abortus infection than C57BL/6 mice at one week post-infection as measured by splenic colonization and splenomegaly. An increase in TCR?? cells was observed in the spleens of B. abortus-infected C57BL/6 mice, which peaked at two weeks post-infection and occurred concomitantly with diminished brucellae. ?? T cells were the major source of IL-17 following infection and also produced IFN-?. Depletion of ?? T cells from C57BL/6, IL-17R?(-/-), and GMCSF(-/-) mice enhanced susceptibility to B. abortus infection although this susceptibility was unaltered in the mutant mice; however, when ?? T cells were depleted from IFN-?(-/-) mice, enhanced susceptibility was observed. Neutralization of ?? T cells in the absence of TNF-? did not further impair immunity. In the absence of TNF-? or ?? T cells, B. abortus-infected mice showed enhanced IFN-?, suggesting that they augmented production to compensate for the loss of ?? T cells and/or TNF-?. While the protective role of ?? T cells was TNF-?-dependent, ?? T cells were not the major source of TNF-? and activation of ?? T cells following B. abortus infection was TNF-?-independent. Additionally, bovine TCR?? cells were found to respond rapidly to B. abortus infection upon co-culture with autologous macrophages and could impair the intramacrophage replication of B. abortus via IFN-?. Collectively, these results demonstrate ?? T cells are important for early protection to B. abortus infections.

| S-EPMC3134454 | biostudies-other

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