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Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE151831 | GEO | 2020/07/08

REPOSITORIES: GEO

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Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses [scRNA-seq]

Project description:Therapeutic targeting of immune checkpoint pathways, that are exploited by tumors to evade the immune system, can result in increased overall survival for some patients with specific types of cancers. The endogenous antitumor response is limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring their deletion to protect against autoimmunity. In this study, we show that compared to wild-type mice, tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models and was accompanied by increased numbers of activated T cells expressing high levels of genes such as Gzma, Gzmb, Perforin, Cxcr3, and tumors contained high levels of the chemokines Cxcl9 and Cxcl10 compared to wild-type mice. Furthermore, there was an enrichment of T cells expressing markers associated with the potent anti-tumor tissue-resident memory T cells expressing Cd103. Consistent with Aire’s central role in T cells repertoire selection, single cell TCR sequencing unveiled the expansion of several clones with high tumor reactivity. Together, these results show that a break in central tolerance in combination with immune checkpoint blockade can potently enhance anti-tumor immunity and serve as a model system to unmask novel anti-tumor therapies.

2020-07-08 | GSE151830 | GEO

Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses [bulk RNA-seq]

2020-07-08 | GSE151829 | GEO

Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses

Project description:Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses

| PRJNA637374 | ENA

Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses [scRNA-seq]

Project description:Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses [scRNA-seq]

| PRJNA637451 | ENA

Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses [bulk RNA-seq]

Project description:Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses [bulk RNA-seq]

| PRJNA637450 | ENA

Pulling RANK on Cancer: Blocking Aire-Mediated Central Tolerance to Enhance Immunotherapy.

Project description: Not available

| S-EPMC6550349 | biostudies-literature

LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity.

Project description: Not available

| S-EPMC5087700 | biostudies-other

Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer.

Project description: Not available

| S-EPMC4268177 | biostudies-literature

Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models.

Project description: Not available

| S-EPMC4674486 | biostudies-literature

Sirt1 is essential for Aire-mediated induction of central immunological tolerance

Project description:Autoimmune regulator (Aire) is a unique transcriptional regulator that induces promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for induction of immunological self-tolerance. Although several recent studies provided very important molecular insights into how Aire operates, a more comprehensive understanding of this process still remains elusive. Here we demonstrate that a lysine deacetylase Sirtuin-1 (Sirt1) is predominantly expressed in mature Aire+ mTECs, where it is required for expression of Aire-dependent TRA genes and a subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and uncovers a unique functional role for Sirt1 in preventing organ-specific autoimmunity. ~100ng of total RNA isolated by Trizol extraction from MHC-II low and high mTECs (pool of 3 mice) was used to generate poly-A-selected transcriptome libraries using the non-directionnal TruSeq V3 RNA Sample Prep Kit (without additional pre-amplification) following the manufacturer's protocols. Enrichment of DNA fragment with adapter molecules on both ends was done using 15 cycles of PCR amplification using the Illumina PCR mix and primer cocktail. Paired-end (2 × 100 bp) sequencing was performed using the Illumina HiSeq2000 machine.

2015-05-25 | E-GEOD-68190 | biostudies-arrayexpress

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