scholarly journals Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells

2021 ◽  
Author(s):  
Yuhao Shi ◽  
Melissa Dolan ◽  
Michalis Mastri ◽  
James W. Hill ◽  
Adam Dommer ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Ex Vivo ◽  
Gene Knockout ◽  
Acquired Resistance ◽  
Mouse Tumor ◽  
Type I ◽  
Type I Ifn ◽  
Signaling Crosstalk

Therapeutic inhibition of programmed cell death ligand (PD-L1) can reverse PD-1-mediated suppression of tumor-killing T-cells; however, many patients develop resistance. Acquired resistance may be derived from intracellular PD-L1 and interferon (IFN) signaling programs in the tumor that can have dual, sometimes opposing, influences on tumor immune responses. Here we show that PD-L1 inhibition induces a novel secretory program tightly controlled by IFN-signaling and specific to acquired, but not innate, resistance in tumors. A PD-L1 treatment-induced secretome (PTIS) was found to be enriched for several IFN-stimulated genes (ISGs) and then further enhanced by type I IFN stimulation (IFNα or IFNβ) in multiple mouse tumor models. Chronic inhibition or gene knockout of tumor PD-L1 in vitro could elicit similar type I IFN-enhanced secretory stimulation while resistant cells were able to suppress T cell activation and killing ex vivo. When reimplanted into mice, resistant tumors were more sensitive to IL-6 inhibition (a key PTIS component) and growth significantly reduced when type I IFN signaling was blocked. Together, these results show that prolonged PD-L1 inhibition can 'rewire' existing intracellular IFN:PD-L1 signaling crosstalk to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.

scholarly journals GABAA receptor α4-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model

2017 ◽  
Vol 313 (2) ◽  
pp. L406-L415 ◽  
Author(s):  
Gene T. Yocum ◽  
Damian L. Turner ◽  
Jennifer Danielsson ◽  
Matthew B. Barajas ◽  
Yi Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Asthma Model

Emerging evidence indicates that hypnotic anesthetics affect immune function. Many anesthetics potentiate γ-aminobutyric acid A receptor (GABAAR) activation, and these receptors are expressed on multiple subtypes of immune cells, providing a potential mechanistic link. Like immune cells, airway smooth muscle (ASM) cells also express GABAARs, particularly isoforms containing α4-subunits, and activation of these receptors leads to ASM relaxation. We sought to determine if GABAAR signaling modulates the ASM contractile and inflammatory phenotype of a murine allergic asthma model utilizing GABAAR α4-subunit global knockout (KO; Gabra40/0) mice. Wild-type (WT) and Gabra4 KO mice were sensitized with house dust mite (HDM) antigen or exposed to PBS intranasally 5 days/wk for 3 wk. Ex vivo tracheal rings from HDM-sensitized WT and Gabra4 KO mice exhibited similar magnitudes of acetylcholine-induced contractile force and isoproterenol-induced relaxation ( P = not significant; n = 4). In contrast, in vivo airway resistance (flexiVent) was significantly increased in Gabra4 KO mice ( P < 0.05, n = 8). Moreover, the Gabra4 KO mice demonstrated increased eosinophilic lung infiltration ( P < 0.05; n = 4) and increased markers of lung T-cell activation/memory (CD62L low, CD44 high; P < 0.01, n = 4). In vitro, Gabra4 KO CD4+ cells produced increased cytokines and exhibited increased proliferation after stimulation of the T-cell receptor as compared with WT CD4+ cells. These data suggest that the GABAAR α4-subunit plays a role in immune cell function during allergic lung sensitization. Thus GABAAR α4-subunit-specific agonists have the therapeutic potential to treat asthma via two mechanisms: direct ASM relaxation and inhibition of airway inflammation.

scholarly journals Age-Associated Failure To Adjust Type I IFN Receptor Signaling Thresholds after T Cell Activation

2015 ◽  
Vol 195 (3) ◽  
pp. 865-874 ◽  
Author(s):  
Guangjin Li ◽  
Jihang Ju ◽  
Cornelia M. Weyand ◽  
Jörg J. Goronzy
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Type I ◽  
Receptor Signaling ◽  
Type I Ifn ◽  
Signaling Thresholds

scholarly journals 084 UVB induces prolonged T cell activation in lupus-prone mice via type I IFN inhibition of T regulatory cells

2019 ◽  
Vol 139 (5) ◽  
pp. S14
Author(s):  
S. Wolf ◽  
S.N. Estadt ◽  
J. Theros ◽  
T. Moore ◽  
J. Ellis ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Regulatory Cells ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Cells

scholarly journals Analysis of type I IFN response and T cell activation in severe COVID-19/HIV-1 coinfection

Medicine ◽  
2020 ◽  
Vol 99 (36) ◽  
pp. e21803 ◽  
Author(s):  
Gabriella d’Ettorre ◽  
Gregorio Recchia ◽  
Marco Ridolfi ◽  
Guido Siccardi ◽  
Claudia Pinacchio ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Type I ◽  
Type I Ifn ◽  
Hiv 1

scholarly journals Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation

2015 ◽  
Vol 112 (45) ◽  
pp. 13994-13999 ◽  
Author(s):  
Wei Hu ◽  
Aakanksha Jain ◽  
Yajing Gao ◽  
Igor M. Dozmorov ◽  
Rajakumar Mandraju ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Type I ◽  
Type I Ifn ◽  
Important Distinction ◽  
Type I Ifns ◽  
Mitogen Activated Protein ◽  
Dc Maturation

Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation, a process involving up-regulation of MHC and costimulatory molecules and secretion of proinflammatory cytokines. All TLRs except TLR3 achieve these outcomes by using the signaling adaptor myeloid differentiation factor 88. TLR4 and TLR3 can both use the Toll–IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-dependent signaling pathway leading to IFN regulatory factor 3 (IRF3) activation and induction of IFN-β and -α4. The TRIF signaling pathway, downstream of both of these TLRs, also leads to DC maturation, and it has been proposed that the type I IFNs act in cis to induce DC maturation and subsequent effects on adaptive immunity. The present study was designed to understand the molecular mechanisms of TRIF-mediated DC maturation. We have discovered that TLR4–TRIF-induced DC maturation was independent of both IRF3 and type I IFNs. In contrast, TLR3-mediated DC maturation was completely dependent on type I IFN feedback. We found that differential activation of mitogen-activated protein kinases by the TLR4– and TLR3–TRIF axes determined the type I IFN dependency for DC maturation. In addition, we found that the adjuvanticity of LPS to induce T-cell activation is completely independent of type I IFNs. The important distinction between the TRIF-mediated signaling pathways of TLR4 and TLR3 discovered here could have a major impact in the design of future adjuvants that target this pathway.

scholarly journals Analysis of Th17 and Tc17 Frequencies and Antiviral Defenses in Gut-Associated Lymphoid Tissue of Chronic HIV-1 Positive Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Gabriella d’Ettorre ◽  
Giancarlo Ceccarelli ◽  
Mauro Andreotti ◽  
Carla Selvaggi ◽  
Noemi Giustini ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Lymphoid Tissue ◽  
Cell Activation ◽  
Immune Cell ◽  
Effector Memory ◽  
Type I ◽  
Type I Ifn ◽  
Immune Cell Activation ◽  
Blood Compartment ◽  
Hiv 1

The complex relationship between both the Th1/Th17 and Tc1/Tc17 axis and innate defences in the intestinal mucosa during HIV-1 infection has not been well characterized. This study examined the frequency, phenotype, and functional status of T cell populations in the gut-associated lymphoid tissue and peripheral blood of virologically suppressed HIV-1-infected patients on therapy, focusing on the Th1, Th17, Tc1, and Tc17 cell subsets. We found a persistent immune cell activation (CD38 and HLADR expression) into the GALT despite the higher levels of Th17 and Tc17 in respect to peripheral blood. An upregulation of type I IFN response in GALT compared to the peripheral blood compartment was also recorded. Furthermore, IFN-α/βlevels were negatively related to the frequencies of Th1 naïve cells and Tc1 cell subsets (naïve, central memory, and effector memory) in the GALT. In contrast, no relationships between type I IFN response and Th1 or Tc1 cell subsets in peripheral blood compartment and between IFN-α/βand Th17/Tc17 in both GALT and peripheral blood district were recorded. These data indicate that prolonged antiretroviral treatment improves GALT immune function despite the persistence of immune activation and type I IFN response in chronic HIV-1 positive patients.

scholarly journals 886 Targeting VSIG4, a novel macrophage checkpoint, repolarizes suppressive macrophages which induces an inflammatory response in primary cell in vitro assays and fresh human tumor cultures

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A928-A928
Author(s):  
Steve Sazinsky ◽  
Phuong Nguyen ◽  
Mohammad Zafari ◽  
Ryan Phennicie ◽  
Joe Wahle ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Ex Vivo ◽  
Syngeneic Mouse ◽  
Pathogen Clearance

BackgroundVSIG4 (V-set immunoglobulin-domain-containing 4) is a B7 family related protein with known roles as a complement receptor involved in pathogen clearance as well as a negative regulator of T cell activation by an undetermined mechanism.1–3 VSIG4 is expressed in tumor associated macrophages (TAMs) with exquisite specificity. In cancer, increased expression of VSIG4 has been associated with worse survival in multiple indications, including non-small cell lung cancer, multiple myeloma, ovarian cancer, and glioma, suggesting an important role in tumor immune evasion.3–6 Based upon computational analysis of transcript data across thousands of primary cancer and normal tissue samples, we hypothesized that VSIG4 has an important regulatory role in promoting M2-like immune suppressive macrophages in the tumor microenvironment, and that targeting VSIG4 via a monoclonal antibody could relieve VSIG4-mediated macrophage suppression by repolarizing TAMs to an inflammatory phenotype capable of coordinating an anti-tumor immune response.MethodsThe ability of anti-VSIG4 antibodies to repolarize M2-like macrophages and induce T cell activation was assessed in vitro and ex vivo, by measuring production of inflammatory mediators. In vitro assays were performed primarily with M-CSF plus IL-10 driven monocyte-derived M2c macrophages from healthy donors. Ex vivo assays were performed with fresh, patient-derived tumor samples in culture. To determine whether targeting VSIG4 can lead to an anti-tumor effect in vivo, syngeneic mouse models were dosed with anti-mouse VSIG4 antibodies and characterized for changes in tumor volume and immune cell populations.ResultsIn in vitro and ex vivo assays anti-VSIG4 antibodies repolarize M2 macrophages and induce an immune response culminating in T cell activation. Targeting VSIG4 upregulates pro-inflammatory cytokines in M2c macrophages, as well as upregulates pro-inflammatory myeloid-derived cytokines and T cell-derived cytokines in M2c macrophages co-cultured with autologous T cells in the presence of staphylococcal enterotoxin B (SEB) activation. To assess targeting VSIG4 in a relevant translational model, fresh, patient-derived tumor samples were treated ex vivo with anti-VSIG4. Across multiple tumor types, anti-VSIG4 treatment resulted in a significant upregulation of cytokines involved in TAM repolarization and T cell activation, and chemokines involved in immune cell recruitment, at levels greater than observed by treatment with anti-PD-1 or a clinical macrophage repolarizing agent (anti-ILT-4). In vivo, tumor growth inhibition is observed in syngeneic mouse models dosed with anti-mouse-VSIG4 alone and in combination with anti-PD-1.ConclusionsTaken together, these data suggest that VSIG4 represents a promising new target capable of stimulating an anti-cancer response via multiple key immune mechanisms.Referencesvan Lookeren Campagne M, Verschoor A. Pathogen clearance and immune adherence “revisited”: immuno-regulatory roles for CRIg. Semin Immunol 2018;37:4–11.Xu S, Sun Z, Li L, Liu J, He J, Song D, Shan G, Liu H, Wu X. Induction of T cells suppression by dendritic cells transfected with VSIG4 recombinant adenovirus. Immunol Lett 2010;128(1):46–50.Liao Y, Guo S, Chen Y, Cao D, Xu H, Yang C, Fei L, Ni B, Ruan Z. VSIG4 expression on macrophages facilitates lung cancer development. Lab Invest 2014;94(7):706–715.Roh J, Jeon Y, Lee A, Lee S, Kim Y, Sung C, Park C, Hong J, Yoon D, Suh C, Huh J, Choi I, Park C. The immune checkpoint molecule V-set Ig domain-containing 4 is an independent prognostic factor for multiple myeloma. Oncotarget 2017;8(35):58122–58132.Xu T, Jiang Y, Yan Y, Wang H, Lu C, Xu H, Li W, Fu D, Lu Y, Chen J. VSIG4 is highly expressed and correlated with poor prognosis of high-grade glioma patients. Am J Transl Res 2015;7(6):1172–1180.Byun J, Jeong D, Choi I, Lee D, Kang M, Jung K, Jeon Y, Kim Y, Jung E, Lee K, Sung M, Kim K. The significance of VSIG4 expression in ovarian cancer. Int J Gynecol Cancer 2017;27(5):872–878.Ethics ApprovalAll legal and ethical requirements were met with regards to the humane treatment of animals described in the study. The animal study was conducted in compliance with CRL IACUC under IACUC No. I033.

scholarly journals Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

2019 ◽  
Author(s):  
Jie Wang ◽  
Tariq Hussain ◽  
Kai Zhang ◽  
Yi Liao ◽  
Jiao Yao ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Defense Mechanism ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Pathways ◽  
Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination.Viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

scholarly journals Type I interferon dependence of plasmacytoid dendritic cell activation and migration

2005 ◽  
Vol 201 (7) ◽  
pp. 1157-1167 ◽  
Author(s):  
Carine Asselin-Paturel ◽  
Géraldine Brizard ◽  
Karine Chemin ◽  
Andre Boonstra ◽  
Anne O'Garra ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Type I Interferon ◽  
Ex Vivo ◽  
Plasmacytoid Dendritic Cell ◽  
Type I ◽  
Cell Area ◽  
Type I Ifn ◽  
And Migration

Differential expression of Toll-like receptor (TLR) by conventional dendritic cells (cDCs) and plasmacytoid DC (pDCs) has been suggested to influence the type of immune response induced by microbial pathogens. In this study we show that, in vivo, cDCs and pDCs are equally activated by TLR4, -7, and -9 ligands. Type I interferon (IFN) was important for pDC activation in vivo in response to all three TLR ligands, whereas cDCs required type I IFN signaling only for TLR9- and partially for TLR7-mediated activation. Although TLR ligands induced in situ migration of spleen cDC into the T cell area, spleen pDCs formed clusters in the marginal zone and in the outer T cell area 6 h after injection of TLR9 and TLR7 ligands, respectively. In vivo treatment with TLR9 ligands decreased pDC ability to migrate ex vivo in response to IFN-induced CXCR3 ligands and increased their response to CCR7 ligands. Unlike cDCs, the migration pattern of pDCs required type I IFN for induction of CXCR3 ligands and responsiveness to CCR7 ligands. These data demonstrate that mouse pDCs differ from cDCs in the in vivo response to TLR ligands, in terms of pattern and type I IFN requirement for activation and migration.

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