Inhibition of SUMOylation Induces Adaptive Anti-Tumor Immunity Against Pancreatic Cancer through Multiple Effects on the Tumor Microenvironment
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ABSTRACT:
PROVIDER: PRJNA875436 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21380746_1.fastq.gz | Fastqsanger.gz | |||
| SRR21380746_2.fastq.gz | Fastqsanger.gz | |||
| SRR21380747_1.fastq.gz | Fastqsanger.gz | |||
| SRR21380747_2.fastq.gz | Fastqsanger.gz | |||
| SRR21380748_1.fastq.gz | Fastqsanger.gz |
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Project description:Improvement of pancreatic ductal adenocarcinoma (PDAC) patients’ outcomes require exploration of novel therapeutic mechanisms. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment (TME) are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical stage compound, TAK-981. TAK-981 monotherapy improved survival in immunocompetent mice. However, in contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit of TAK-981 in vivo is dependent on the presence of T cells. Induction of adaptive anti-tumor immunity is the dominant anti-tumor effect of SUMOylation inhibition in vivo. To elucidate the mechanism of adaptive immunity, we performed comparative single cell transcriptomics analyses of murine and human PDAC tumors, including cancer cells, T cells, tumor associated macrophages (TAM) and cancer associated fibroblasts (CAF), in combination with immunofluorescence, immunohistochemistry, western blots and qPCR. Mechanistically, SUMOylation regulates T cell activation and differentiation. In addition, TAK-981 changed gene expression in TAM, CAF and cancer cells that are likely to enhance the anti-tumor T cell response. These findings provide rationale for combination strategies to augment adaptive immune responses to PDAC that are necessary for durable disease control in PDAC patients.
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Project description:Tumor suppressor p14ARF is a lysine-less protein that suppresses tumorigenesis through different mechanisms, including enhancing the SUMOylation of its interactors. Although p14ARF is known to interact with the SUMO conjugating enzyme UBC9, the link between ARF and SUMOylation is poorly understood and the potential impact of SUMOylation on p14ARF is unknown. Herein, we show that p14ARF is modified by SUMO2 in vitro, both in transfected cells and under endogenous conditions. SUMO conjugates to the N-terminal part of the tumor suppressor protein increasing its stability. Degradation of p14ARF protein is induced by UBC9 downmodulation or the inhibition of SUMOylation, and is rescued by the NEDDylation inhibitor MLN4924. Treatment with MLN4924 also promotes p14ARF SUMOylation and the transcriptional transactivation of the SUMOylation machinery components SUMO1, SUMO2 and UBC9. This causes a global increase in SUMOylation that contributesto the upregulation of p14ARF levels. Importantly, p14ARF is required for the global increase in SUMOylation induced by MLN4924, and it plays an important role in the cytotoxic effect of the NEDDylation inhibitor on prostate cancer cells. Our results provide evidence that lysine-independent SUMOylation of p14ARF is a new post-translational mechanism regulating p14ARF stability and establishes a new link between inhibition of NEDDylation and SUMOylation.
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Project description:Clinical benefit remains elusive for most patients with poorly inflamed carcinomas treated with immune checkpoint blockade. Alternative therapies able to convert the tumor microenvironment (TME) into a functionally inflamed immune hub may increase clinical benefit. Using comprehensive TME single-cell transcriptome, proteome, and immune cell analysis, we demonstrated that entinostat, a class I HDAC inhibitor, facilitates tumor deposition of the necrosis-targeted immunocytokine NHS-IL12 to promote potent anti-tumor efficacy against established MC38 and CT26 colon carcinoma models, with complete eradication of poorly immunogenic EMT6 breast tumors. Combination therapy reprogrammed the tumor innate and adaptive immunome to an inflamed landscape, where the concerted action of highly functional CD8+ T cells and activated neutrophils drove a dramatic macrophage M1-like polarization leading to complete tumor eradication. A biomarker signature of the mechanism involved in these studies is associated with patients’ overall survival in multiple tumor types. Collectively, these findings provide a rationale for combining NHS-IL12 with entinostat in the clinical setting.
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Project description:A balanced SUMOylation equilibrium safeguards the functional anti-tumor immune response. Oncogene activation drives SUMOylation, rendering aberrant SUMOylation a hallmark of cancer. To delineate the impact of activated SUMOylation on the tumor-immune synapse, we applied HLA class-I-targeted ligandomics and identified a function of activated SUMOylation in restricting the immunopeptidome landscape. Importantly, aberrant SUMOylation suppressed a unique HLA-I peptide and oncoprotein-derived neoepitope repertoire, enabling cancer cells to evade T cell immune surveillance. Mechanistically, SUMOylation impaired the immunoproteasome constitution and proteolytic activity, thus limiting the diversity of the peptide landscape. Further, SUMOylation altered TAP1 transporter binding preferences, thereby mimicking viral immune evasion strategies. As an actionable application, pharmacological inhibition of SUMOylation unmasked the targetable immunopeptidome and enhanced the tumor cell susceptibility to T cell killing. These findings highlight SUMOylation as a critical regulator of the adaptive anti-tumor immune response. We propose SUMO inhibition as a strategic approach to enhance immunogenic peptide presentation, thereby improving the efficacy of cancer immunotherapies.
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Project description:Colorectal and pancreatobiliary cancers are the most common digestive cancers. Their incidence has particularly increased over the last few decades, leading to suspicion that environmental factors are involved. In addition, strategies for the therapeutic management of these cancers are evolving in the context of the development of immunotherapies.
Tumor microenvironment is a potential source of new diagnostic, prognostic and predictive markers and new therapeutic targets. The links between tumor microenvironment and modulation of the immune system in colorectal and pancreatobiliary cancers are poorly understood. Molecular classifications have been proposed for these cancers, but their link with immunity and response to treatment remains to be explored.
Objective : explore links between molecular subtypes, tumor microenvironment, host (immune system, pre-metastatic niche, intestinal microbiota, metabolism), and survival (prognostic value), response (predictive value) and tolerance (toxicities) to treatments in digestive cancers, in particular colorectal and pancreatobiliary cancers.
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Project description:Background & aimsFusobacterium nucleatum (FN) plays a pivotal role in the development and progression of colorectal cancer by modulating antitumor immune responses. However, the impact of FN on immune regulation in the tumor microenvironment has not been fully elucidated.MethodsThe abundance of FN was measured in 99 stage III CRC tumor tissues using quantitative polymerase chain reaction. Gene expression profiles were assessed and annotated using consensus molecular subtypes (CMS), Gene Ontology (GO) analysis, and deconvolution of individual immune cell types in the context of FN abundance. Immune profiling for tumor infiltrating T cells isolated from human tumor tissues was analyzed using flow cytometry. Ex vivo tumor-infiltrating T cells were stimulated in the presence or absence of FN to determine the direct effects of FN on immune cell phenotypes.ResultsGene expression profiles, CMS composition, abundance of immune cell subtypes, and survival outcomes differed depending on FN infection. We found that FN infection was associated with poorer disease-free survival and overall survival in stage III CRC patients. FN infection was associated with T cell depletion and enrichment of exhausted CD8+ and FoxP3+ regulatory T cells in the tumor microenvironment. The presence of FN in tumors was correlated with a suppressive tumor microenvironment in a T cell-dependent manner.ConclusionFN enhanced the suppressive immune microenvironment with high depletion of CD8+ T cells and enrichment of FoxP3+ regulatory T cells in human colorectal cancer cases. Our findings suggest a potential association for FN in adaptive immunity, with biological and prognostic implications.
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