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Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity

ABSTRACT: Tumor-infiltrating antigen-presenting cells, such as dendritic cells (DC), have the capacity to shape anti-tumor T cell responses. While tremendous progress has been made in unraveling the role of Batf3-driven DC1 in the anti-tumor immune response, the contributions of other tumor-infiltrating DC subsets remain poorly understood. Furthermore, tumor-infiltrating DC exist in a range of functional states with differential impacts on anti-tumor immunity. In this study, we sought to identify and characterize the functionally relevant DC states associated with a productive anti-tumor T cell response. By comparing the DC infiltrate of spontaneously regressing tumors and progressing tumors, we identified a novel activation state of CD11b+ conventional DC in tumors, which expressed an interferon-stimulated gene signature (‘ISG+ DC’). ISG+ DC were activated by type-I-interferon-induced signaling and could generate protective CD8+ T cell responses by cross-dressing with tumor-derived peptide-MHC complexes. Stimulatory ISG+ DC induced by exogenous IFNβ addition drove robust anti-tumor T cell responses in poorly immunogenic tumors even in the absence of DC1.

ORGANISM(S): Mus musculus

PROVIDER: GSE181938 | GEO | 2022/01/13

REPOSITORIES: GEO

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Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity

Project description:Tumor-infiltrating antigen-presenting cells, such as dendritic cells (DC), have the capacity to shape anti-tumor T cell responses. While tremendous progress has been made in unraveling the role of Batf3-driven DC1 in the anti-tumor immune response, the contributions of other tumor-infiltrating DC subsets remain poorly understood. Furthermore, tumor-infiltrating DC exist in a range of functional states with differential impacts on anti-tumor immunity. In this study, we sought to identify and characterize the functionally relevant DC states associated with a productive anti-tumor T cell response. By comparing the DC infiltrate of spontaneously regressing tumors and progressing tumors, we identified a novel activation state of CD11b+ conventional DC in tumors, which expressed an interferon-stimulated gene signature (‘ISG+ DC’). ISG+ DC were activated by type-I-interferon-induced signaling and could generate protective CD8+ T cell responses by cross-dressing with tumor-derived peptide-MHC complexes. Stimulatory ISG+ DC induced by exogenous IFNβ addition drove robust anti-tumor T cell responses in poorly immunogenic tumors even in the absence of DC1.

2022-01-13 | GSE151990 | GEO

Identification of a DC1 immuno-regulatory module that limits antitumor CD8+ T cell immunity in lung cancer lesions.

Project description:While conventional dendritic cells (DC)1 and DC2 are found in tumors, DC1 were shown to control tumor response to checkpoint blockade in preclinical models and are associated with better overall survival in cancer patients, reflecting their specialized ability to prime CD8+ T cell responses. Paradoxically, DC1 can also be found in tumors that resist checkpoint blockade, suggesting that, like many tumor infiltrating T cells, DC1 functionality may be altered in tumors. To address this question, we performed scRNAseq analyses to characterize DC gene architecture in mouse non-small cell lung cancer (NSCLC) lesions. To understand the relationship of the resulting transcriptional signatures with antigen uptake and migration, we profiled lung DCs in CCR7-/- mice, or DCs that had taken up (i) GFP from GFP-expressing tumors that had been seeded in the lung, and (ii) fluorescent microbeads that had been applied intranasally.

2020-03-26 | GSE131957 | GEO

Transcription factor Etv6 controls functional differentiation of cross-presenting classical dendritic cells [RNA-Seq]

Project description:An IRF8-dependent subset of classical dendritic cells (cDCs), termed DC1, effectively cross-primes CD8+ T cells and facilitates antitumor T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function. We report that like HSPC, cDCs express Etv6 but not its antagonist ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow reduced the generation of DC1-like cells in vitro and the differentiation of DC1 in vivo, including the loss of signature marker CD8a. Global expression and chromatin profiling of Etv6-deficient DCs revealed impaired lineage identity of DC1, including the reduction of cDC signature and upregulation of pDC signature. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and tumor-specific CD8+ T cell responses. These results identify Etv6 as a regulator of DC1 differentiation and functional fitness that indirectly facilitates T cell cross-priming and antitumor immunity.

2018-08-03 | GSE106406 | GEO

Transcription factor Etv6 controls functional differentiation of cross-presenting classical dendritic cells [ATAC-Seq]

2018-08-03 | GSE106405 | GEO

Tissue-specific interferon-gamma levels drive regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer

Project description:Regulatory T cells (Tregs) are proposed to restrain anti-tumor T cell responses either directly or by suppression of antigen-presenting cells and can act in a tissue-specific manner. Treg abundance is typically reported as a measure of suppression, without consideration of Treg functional quality. Here, we find that Tregs suppress type 1 conventional dendritic cells (DC1) and thereby induce dysfunctional CD8+ T cell responses against lung cancer. This immunoregulatory effect is spatially coordinated within tissue-specific lymph node microniches and requires antigen-specific contact between DC1 and Tregs. Suppressive clonally expanded TH1-like effector Tregs were differentially induced in the lung lymph node in response to tissue-specific levels of interferon-gamma. In cancer patients, TH1-like Tregs but not CD8+/Treg ratios correlate with poor responses to checkpoint blockade immunotherapy. Thus, Tregs that adopt the interferon-gamma-dependent TH1-like effector state have increased potential to restrain tumor-reactive T cell responses and represent a critical barrier to productive anti-tumor immunity.

2022-11-17 | GSE216086 | GEO

Identification of potential substrates of TRABID in HeLa cells using SILAC

Project description:Immune checkpoint blockades (ICBs) have been approved for treating multiple cancer types, but the response rate is limited for many solid tumors. Much efforts have been devoted to understand the mechanisms governing ICB therapy efficacy and the abundance of tumor-infiltrating lymphocytes is among the factors that influence on ICB responsiveness. The deubiquitinase TRABID was identified in our previous study as a positive regulator of autophagy by stabilizing VPS34, the class III PI3K critical for autophagosome formation. In this study, we identify an upregulation of TRABID in mitosis and its critical role in mitotic progression through deubiquitination and stabilization of AURKB and BIRC5, two subunits of the chromosome passenger complex governing multiple mitotic steps. Furthermore, TRABID depletion induces micronuclei phenotype, which is likely mediated by the combinatory defects in mitosis and autophagy. Consequently, TRABID depletion or inhibition activates cGAS/STING pathway to induce type I interferon production and inflammatory responses. TRABID depletion in tumors cells reduces tumor burden and promotes anti-tumor immune surveillance by increasing tumor infiltration of CD4+ and CD8+ T cells and NK cells and reducing Treg cells. Clinically, TRABID expression in multiple cancer types correlates negatively with the infiltration of anti-tumor immune cells and positively with that of pro-tumor immune cells. Our study supports a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and suggests TRABID inhibitor as a promising agent for enhancing the sensitivity of solid tumors to ICB therapy.

2023-05-11 | PXD035002 | Pride

Single cell analysis informs efficient reprogramming of human somatic cells to dendritic cells type 1

Project description:Type-1 dendritic cells (DC1s) are critical cellular mediators of anti-tumor immunity, as their ability to prime CD8+ T-cells is crucial for response to checkpoint blockade and adoptive T-cell transfer. Vaccination strategies to harness this unique DC subset for immunotherapy have been limited by their rarity in peripheral blood and lack of homogeneous alternative cell sources. We have previously identified PU.1, IRF8 and BATF3 transcription factors (TF) as sufficient to induce DC1 program in mouse fibroblasts but reprogramming efficiency in human cells was low. Here, we investigated single-cell transcriptional dynamics during human DC1 reprogramming. Human induced DC1s (hiDC1s) generated from embryonic fibroblasts acquire global DC1 transcriptional profile and activate antigen presentation signatures. Interestingly, other DC subsets are not induced at the single cell level. We extracted gene modules associated with successful reprogramming and identified inflammatory signaling and the DC1 reprogramming TF network as key drivers of the process. Combining inflammatory cytokine signaling with TF constitutive overexpression lead to improved reprogramming efficiency by 190-fold. HiDC1s acquire the ability to uptake dead cells, respond to stimuli, secrete inflammatory cytokines and perform antigen presentation. Remarkably, intra-tumoral vaccination in mouse models increased infiltration of antigen-specific CD8+ T-cells, promoted a T-cell cytotoxic profile and conferred protection against tumor growth. Finally, we demonstrated efficient hiDC1 generation from human adult somatic cells including dermal fibroblasts and mesenchymal stem cells with a xeno-free protocol. These findings provide insights into human DC1 specification and reprogramming and represent a platform for generating patient-specific DC1s, a long-sought DC subset for cancer immunotherapy.

2022-03-08 | GSE189612 | GEO

RNA-seq of blood from donors with connective tissue diseases in the Lupus Extended Phenotype Cohort

Project description:The connective tissue diseases (CTDs) are group of inflammatory disorders with overlapping clinical and serological manifestations. We have undertaken Lupus Extended Phenotype (LEAP) study in of a cohort of adult patients with CTDs, namely systemic lupus erythematosus, Sjogren's syndrome, mixed and undifferentiated CTD, limited and diffuse cutaneous systemic sclerosis and dermatomyositis. RNAseq was undertaken in 12 participants from 4 ‘cohorts’ based on interferon stimulated gene and autoantibodies analyses: 3 ISG positive and anti-Smith positive participants; 3 ISG positive and anti-Smith negative participants; 3 ISG negative and anti-Smith positive participants and 3 ISG negative and anti-Smith negative participants.

2019-06-05 | E-MTAB-7080 | biostudies-arrayexpress

Antibody-mediated blockade of the IL-23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy

Project description:Regulatory T cells (Treg) can impede anti-tumor immunity and currently represent a major obstacle to effective cancer immunotherapy. Targeting tumor-infiltrating regulatory Treg while sparing systemic Treg represent optimal approaches to this problem. Here, we provide evidence that the interleukin 23 receptor (IL23R) expressed by tumor-infiltrating Treg promotes suppressive activity. Disruption of the IL23R results in increased responsiveness of destabilized Treg to the IL-12 cytokine, production of g-interferon (IFNg) and recruitment of CD8 T cells that inhibit tumor growth. Since the Treg destabilization pathway that is initiated by IL23R blockade is distinct and independent from the destabilization pathway coupled to Glucocorticoid-Induced TNFR-Related protein (GITR) activation, we examined the impact of coordinate induction of the two destabilization pathways on anti-tumor immune responses. Combined GITR and IL23R antibody treatment of mice inoculated with MC38 tumors resulted in robust and synergistic anti-tumor responses. These findings indicate that delineation of independent Treg destabilization pathways may allow improved approaches to the development of combination immunotherapy for cancers.

2022-05-02 | GSE197287 | GEO

Metabolic modulation of tumors with engineered bacteria for immunotherapy

Project description:The availability of L-arginine in tumors is a key determinant of an efficient anti-tumor T cell response. Consequently, elevation of typically low L-arginine levels within the tumor may greatly potentiate the anti-tumor responses of immune checkpoint inhibitors, such as PD-L1 blocking antibodies. However, currently no means are available to locally increase intra-tumoral L-arginine levels. Here, we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumors and continuously converts ammonia, a metabolic waste product that accumulates in tumors, into L-arginine. Colonization of tumors with these bacteria elevated intra-tumoral L-arginine concentrations, increased the amount of tumor-infiltrating T cells, and had striking synergistic effects with PD-L1 blocking antibodies in the clearance of tumors. The anti-tumor effect of the living therapeutic was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumor microenvironment leading to enhanced efficacy of immunotherapies.

2021-07-13 | PXD027167 | Pride

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