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HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity

ABSTRACT: HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity

PROVIDER: PRJNA743304 | ENA |

REPOSITORIES: ENA

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HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity

Project description:Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrate that delivery of class I histone deacetylase inhibitor, MS-275, promotes sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We find that MS-275 alters the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ dendritic cells and depletion of regulatory T cells. Activated endogenous CD8+ T cell responses against non-target tumor antigens was critically required for the prevention of tumor recurrence. Importantly, MS-275 alters the immunodominance hierarchy by directing epitope spreading towards endogenous retroviral tumor-associated antigen, p15E. Our data suggest that MS-275 multi-mechanistically improves epitope spreading to promote long-term clearance of solid tumors.

2021-07-03 | GSE179337 | GEO

HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity.

Project description:Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrated that delivery of the class I histone deacetylase inhibitor MS-275 promoted sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We found that MS-275 altered the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ DCs and depletion of Tregs. Activated endogenous CD8+ T cell responses against nontarget tumor antigens were critically required for the prevention of tumor recurrence. Importantly, MS-275 altered the immunodominance hierarchy by directing epitope spreading toward the endogenous retroviral tumor-associated antigen p15E. Our data suggest that MS-275 in combination with ACT multimechanistically enhanced epitope spreading and promoted long-term clearance of solid tumors.

| S-EPMC9525113 | biostudies-literature

Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis

Project description:This SuperSeries is composed of the following subset Series: GSE32016: Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis [ANALYTE: ANTIGEN] GSE32019: Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis [ANALYTE: Cytokine or chemokine] Refer to individual Series

2011-09-09 | E-GEOD-32021 | biostudies-arrayexpress

Antigen presentation by B cells enables epitope spreading across an MHC barrier

Project description:A progressive increase in the breadth and specificity of autoantibodies over time, termed epitope spreading, drives pathogenic targeting of an ever-widening repertoire of self-components in many autoimmune diseases. Ostensibly, this progressive inclusion of additional B cell clones into an ongoing autoreactive response can occur through linked recognition, whereby proto-autoreactive B cells recognize distinct antigenic epitopes, which carry shared T cell epitopes. In a murine model displaying epitope spreading resembling that observed in systemic lupus erythematosus, we find that the epitope spreading process is compartmentalized by MHC. Antigen presentation by B cells carrying two MHC haplotypes can bridge the MHC barrier between two compartments of B cells that do not share MHC haplotypes, by communicating with two separate pools of MHC-restricted T cells. This leads to inclusion of distinct and diverse B cell reactivities in germinal centers. Our findings demonstrate a formidable capacity of B cells to drive the autoreactive response.

2022-07-01 | GSE202358 | GEO

Antigen presentation by B cells enables epitope spreading across an MHC barrier

Project description:Antigen presentation by B cells enables epitope spreading across an MHC barrier

| PRJNA835703 | ENA

Histone deacetylase inhibitors (HDACi) enhance oncolytic herpes simplex virus in malignant meningioma.

Project description:Histone deacetylase inhibitors (HDACi) enhance oncolytic herpes simplex virus in malignant meningioma.

| PRJNA864618 | ENA

Histone deacetylase inhibitors (HDACi) enhance oncolytic herpes simplex virus in malignant meningioma.

Project description:The goal of the study was to determine whether low dose HDACi sensitizes human malignant meningioma cells to the cytotoxic capacity of oncolytic herpes simplex virus G47delta. RNA sequencing was used to examine transcriptomic changes mediated by HDACi preexposure before oncolytic virus infection.

2022-08-02 | GSE210178 | GEO

Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis

Project description:Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis

| PRJNA147513 | ENA

TCR repertoire analysis reveals increased host CTL diversity induced by CD8a ALN-1

Project description:Collectively, these data present evidence that the antitumor response mediated by CD8a ALN-1 correlates with clonal expansion and increased TCR repertoire diversity in the TDLN and the tumor tissue, implying epitope spreading.

2021-11-12 | GSE188583 | GEO

Endogenous retroviruses promote prion-like spreading of proteopathic seeds

Project description:Prion-like spreading of protein misfolding is characteristic for neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like spreading of proteopathic seeds. To identify changes in the proteome of donor cells that might contribute to protein aggregate spreading, we performed mass spectrometry analyses of total cell lysates and donor EV fractions using N2a cells expressing HA epitope-tagged Sup35 NM prion protein at early (P07) and late passages (P16) post cryopreservation. Among the proteins increased in donor cells and EVs upon prolonged culture, we identified mouse endogenous MLV retrovirus proteins to be highly increased.

2023-10-18 | PXD043201 | Pride

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