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Allergic mediator histamine confers immunotherapy resistance in cancer patients via histamine receptor 1 on macrophage

ABSTRACT: Allergic mediator histamine confers immunotherapy resistance in cancer patients via histamine receptor 1 on macrophage

PROVIDER: PRJNA678382 | ENA |

REPOSITORIES: ENA

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Allergic mediator histamine confers immunotherapy resistance in cancer patients via histamine receptor 1 on macrophage

Project description:How to revive anti-tumor immunity in cancer patients is an unmet challenge. Retrospective screening of common medications revealed that patients who took antihistamines during immunotherapy treatment had significantly improved survival. We further uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in tumor microenvironment to cause T-cell dysfunction. HRH1 activation in macrophages inhibits proinflammatory signaling and dysregulates fatty acid metabolism. HRH1 also increases membrane expression of immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) in macrophages, which renders CD8+ T-cells dysfunctional. Knockout HRH1 or antihistamine treatment negated the immunosuppressive activity of the macrophages, revitalized T-cell cytotoxic function, and restored immunotherapy response. Both animal and human data showed that allergy facilitated tumor growth and induced immunotherapy resistance via histamine/HRH1 axis, underscoring the tumor-p rone activity of allergy. These findings demonstrate that pre-existing allergy in cancer patients can dampen response to immunotherapies and warrant perspective investigation of antihistamines as an adjuvant agent for combinatorial immunotherapy.

2020-11-14 | GSE161484 | GEO

Early gene expression changes in peripheral blood leukocytes with rush immunotherapy

Project description:Peripheral blood mononuclear cells (PBMC) were collected from ficoll gradients of whole blood and immediately processed for total RNA and stored at -80oC until use. Blood was from allergic patients at different timepoints pre or post immunotherapy (RIT). Gene expression was compared for the different timepoints. Blood samples were collected from allergic patients before or after rush immunotherapy (RIT), total RNA was prepared and gene expression assessed by Illumina. Samples were collected pre-rush or at 1 week, 7 weeks, 4 months (and for one patient 5 months) after beginning rush immunotherapy. Blood was taken at each timepoint prior to the patient receiving immunotherapy at each timepoint.

2011-12-30 | E-GEOD-29521 | biostudies-arrayexpress

gene expression microarrays of healthy controls and patients with seasonal allergic rhinitis before and after one year of sublingual immunotherapy

Project description:We recruit 4 healthy controls (HC) and 4 patients (P) with seasonal allergic rhinitis before (b) sublingual immunotherapy at the same time and also the same patients after one year (a) of sublingual immunotherapy. Peripheral blood mononuclear cells (PBMCs) obtained from patients and controls were challenged with diluent (D) or allergen (A) extracts from birch pollen at a density of 106 cells/mL for 7 days in RPMI 1640 supplemented with 2 mM L-glutamine, 5% human AB serum, 5 Î¼M Î²â mercaptoethanol and 50 Î¼g/mL gentamicin. CD4+ T cells were isolated using flow cytometry and the quantity and quality of RNA was examined as described before. Gene expression microarrays (Illumina, San Diego, CA, USA) were performed (by using Agilent G4851B SurePrint G3 Hmn 8Ã60K V2 Microarray Kit).

2017-03-31 | E-MTAB-4366 | biostudies-arrayexpress

Acquired resistance to targeted therapy confers cross-resistance to immunotherapy

Project description:Acquired resistance to targeted therapy confers cross-resistance to immunotherapy

| PRJNA548090 | ENA

Effect of Intradermal Immunotherapy (IDIT) injections on gene expression profiles of activated T cells derived from skin biopsy explants

Project description:A Randomized, Placebo-Controlled Trial of Intradermal Allergen Immunotherapy for Grass Pollen Allergy Background: Repeated intradermal injection of grass pollen (nanograms of allergen) suppresses allergen-induced cutaneous late phase responses, in keeping with effects of conventional high dose subcutaneous and sublingual immunotherapy. We evaluated the efficacy and safety of grass pollen intradermal immunotherapy for treatment of allergic rhinitis.Methods: We randomly assigned 93 adults with grass pollen allergic rhinitis to receive 7 pre-seasonal Intradermal allergen immunotherapy injections (containing 7 ng of Phl p 5 major allergen) or histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season. Skin biopsies were taken after the pollen season following an intradermal allergen challenge. Cutaneous late phase responses were measured 4 and either 7, 10 or 13 months post-treatment. Results No difference in the primary endpoint was observed between treatment arms (median difference, 14; 95% confidence interval [CI], -172.5 to 215.1; P=0.80). Amongst secondary endpoints, nasal symptoms measured with daily scores (median difference, 35; 95% CI, 4.0 to 67.5; P=0.03) and visual-analogue scales (median difference, 53; 95% CI, -11.6 to 125.2; P=0.05) were higher in the intradermal treatment group. Intradermal immunotherapy increased serum Phl p-specific IgE (P=0.001) compared to the control arm and T cells cultured from biopsies showed higher and lower surface of surface markers for Type 2 (P=0.04) and Type 1 (P=0.01) T-helper cells, respectively, Interleukin-5 was differentially expressed by microarray (P=0.03). Late phase responses were still inhibited 7 months after treatment (P=0.03) but not at 10-13 months. Conclusions Grass pollen intradermal allergen immunotherapy was not clinically effective but resulted in immunological priming and worsening of allergic rhinitis symptoms.

2017-06-23 | GSE72324 | GEO

Defective transcription elongation in a subset of cancers confers immunotherapy resistance

Project description:Defective transcription elongation in a subset of cancers confers immunotherapy resistance

| PRJNA489885 | ENA

Transcription profiling of wild type and IL13 knock out mice treated with allergen vs. control to investigate the IL13 role in allergic asthma

Project description:The IL-13 is a central mediator of allergic asthma. This project investigates the mechanisms by which IL-13 elicits the symptoms of asthma.

2007-09-29 | E-GEOD-1301 | biostudies-arrayexpress

An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment

Project description:Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9 responsive cell repertoire is still not well defined. Here, we found IL-9 mediates pro-allergic activities by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+/- interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affects the function of lung macrophages by inducing Arg1 activity. Compared to Arg1-deficient lung macrophages, Arg1-expressing macrophages co-express greater amounts of CCL5. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages can recover allergic inflammation that is lost in Il9r-/- mice. In parallel, the elevated expression of IL-9, IL-9R, Arg1 and CCL5 is correlated with disease in asthma patients. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.

2021-11-15 | GSE162898 | GEO

Single-Cell immunoprofiling after immunotherapy for allergic rhinitis reveals functional suppression of pathogenic Th2 cells and clonal conversion

Project description:Background: Allergic rhinitis is a growing problem worldwide and the only treatment that modifies the cause of the disease is antigen-specific immunotherapy; however, its mechanism(s) of action are not fully understood. Objective: Here, we comprehensively investigated the role and changes of antigen-specific T cells before and after sublingual immunotherapy (SLIT) for Japanese cedar pollinosis (JCP). Methods: We cultured PBMCs obtained both before and at one-year after initiating SLIT and used a combination of single-cell RNA sequence and repertoire sequencing. To investigate biomarkers, we used PBMCs from patients participating a phase II/III trial of SLIT tablets for JCP and PBMCs from good and poor responders in outpatients. Results: Antigen-stimulated culturing after SLIT led to clonal expansion of Th2 and Treg cells, and most of these CD4+ T cells retained their CDR3 regions before and after treatment, indicating antigen-specific clonal responses and differentiation secondary to SLIT. However, SLIT reduced the number of clonal functional Th2 cells but increased the Trans-type Th2 cell population that expresses musculin (MSC), TGF-β, and IL-2. Trajectory analysis suggested that SLIT induced clonal differentiation of the Trans-type Th2 cells differentiated into Treg cells. By using real-time PCR, we found that MSC levels increased after 1 year of treatment in the active SLIT group and good responders. Conclusion: The combination of single-cell RNA sequencing and repertoire analysis helped reveal a part of the underlying mechanism— that SLIT promotes the expression of MSC on pathogenic Th2 cells and suppresses their function, and that MSC may be a potential biomarker of SLIT for allergic rhinitis. Clinical implications MSC expression was higher in the group of active patients who were responsive to SLIT, indicating that these molecules may be potential biomarkers of SLIT efficacy.

2022-04-07 | GSE200107 | GEO

Defective transcription elongation in a subset of cancers confers immunotherapy resistance (B16 RNA-Seq)

Project description:Defective transcription elongation in a subset of cancers confers immunotherapy resistance (B16 RNA-Seq)

| PRJNA489889 | ENA