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Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies I

ABSTRACT: Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies I

PROVIDER: PRJNA952195 | ENA |

REPOSITORIES: ENA

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Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies

Project description:Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies

| PRJNA952188 | ENA

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies II

Project description:Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies II

| PRJNA952196 | ENA

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies II

Project description:IFNγ neutralization by the clinically approved monoclonal antibody emapalumab mitigates severe toxicity related to CAR-T therapy Emapalumab does not impair CAR.CD19 T-cell activation signaling

2023-05-04 | GSE228922 | GEO

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies I

2023-05-04 | GSE228921 | GEO

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-04 | GSE228924 | GEO

Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies.

Project description: Not available

| S-EPMC10256701 | biostudies-literature

IFNγ-induced antigen loss in chimeric antigen receptor (CAR)-T cell therapy

Project description:FDA-approved chimeric antigen receptor (CAR)-expressing T cell therapies (CARTs) have revolutionized the treatment of blood cancers. Yet none have been successful for “solid” tumors, such as colorectal cancer (CRC), the 2nd leading cause of cancer deaths. Guanylyl cyclase C (GUCY2C) has emerged as a clinical-stage target for CART and bispecific T-cell engager (BiTE) therapies in CRC. Here, we identified a novel antigen loss mechanism that limits the efficacy of CART in CRC, in which IFNγ secreted by activated CART cells causes bystander cancer cells to lose GUCY2C. Moreover, this previously unexplored antigen loss mechanism is mediated through IFNγR (receptor)/JAK and cellular stress signaling pathways. This newly discovered mechanism of antigen loss can be rescued with anti-IFNγ neutralizing antibody, the JAK inhibitor ruxolitinib, or 4-phenylbutyrate (an ER stress reliever). IFNγ has been canonically recognized as beneficial for the effector functions of T cells by enhancing antigen processing and HLA presentation and is essential for CART targeting of solid malignancies by inducing adhesion molecule expression for synapse stabilization. Here, we revealed a negative effect of IFNγ that uniquely interferes with immunotherapies targeting native surface antigens, such as CART and BiTE therapies, which may be reversed by disrupting stress signaling pathways to enhance solid tumor CART and BiTE immunotherapies.

2026-04-08 | GSE322823 | GEO

IFNγ-independent control of Mycobacterium tuberculosis infection in rhesus macaques

Project description:Control of Mycobacterium tuberculosis (Mtb) infection requires IFNγ in mice. In humans, IFNγ is critical for resistance to non-tuberculous mycobacteria (NTM), but its role in classic pulmonary tuberculosis is less clear. Here we block IFNγR1 signaling in rhesus macaques at different times post-infection. Short-term IFNγ blockade after tuberculoma formation rapidly reduced 18FDG-PET/CT scores of lung inflammation and changed macrophage gene expression. It also increased IFNβ, pDCs, plasma cells, killers and IFN-driven gene expression in neutrophils. Blockade started on the day of infection altered T and B cell responses and reduced cytokine levels in granulomas. Surprisingly, IFNγ blockade did not affect bacterial loads. We also find that patients with anti-IFNγ neutralizing autoantibodies develop extrapulmonary NTM disease, not pulmonary tuberculosis, despite immunological evidence of Mtb exposure. Thus, IFNγ has broad immunomodulatory effects during tuberculosis, especially on antiviral-like responses, but control of pulmonary Mtb infection does not require generating high levels of IFNγ.

2026-02-25 | GSE303154 | GEO

IFNγ-independent control of Mycobacterium tuberculosis infection in rhesus macaques

2026-02-25 | GSE303792 | GEO

UBIQUITIN LIGASE STUB1 DESTABILIZES IFNγ-RECEPTOR COMPLEX TO SUPPRESS TUMOR IFNγ SIGNALING

Project description:The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about 36 regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This was corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response was increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.

2022-03-07 | PXD030580 | Pride

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