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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

UCPVax, a CD4 helper peptide vaccine induces polyfunctional Th1 cells, antibody response and epitope spreading to improve antitumor immunity [TCR-seq]

Project description:The induction of an antitumor CD4+ T helper response is essential for the efficacy of therapeutic cancer vaccines. However, few vaccines are specifically designed to target CD4+ T cells in human cancers. Here, we characterize the immune mechanisms of UCPVax, a helper peptide vaccine derived from telomerase. Ex vivo immune profiling of peripheral blood from 60 patients with advanced lung cancer reveals that UCPVax selectively activates CD4+ T cells in vivo across a broad HLA-DR restriction. The vaccine elicits a synergistic immune triad including cytokine-polyfunctional CD4+ Th1 cells, epitope spreading, and antibody response, contributing to effective tumor control. Single-cell analysis further demonstrates that UCPVax drives CD4+ T cells toward effector-memory and cytolytic differentiation. Thus, the vaccine-induced CD4+T cells trigger a broad and durable antitumor immunity. These findings highlight UCPVax as an off-the-shelf helper platform to enhance therapeutic cancer vaccine efficacy.

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UCPVax, a CD4 helper peptide vaccine induces polyfunctional Th1 cells, antibody response and epitope spreading to improve antitumor immunity [scRNA-seq]

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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 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

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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.

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

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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.

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