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Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy [bulk RNA-seq]

ABSTRACT: Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the Interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE253092 | GEO | 2024/06/27

REPOSITORIES: GEO

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Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy [scRNA-seq]

Project description:Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the Interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy.

2024-06-27 | GSE253093 | GEO

Immunologic and clinical activity to ICB combinations in DAPPER Leiomyosarcoma cohort

Project description:Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pre-treated LMS patients.

2024-01-01 | E-MTAB-12922 | biostudies-arrayexpress

RNA-sequencing analysis of tumor-infiltrating B cells

Project description:Tumour-infiltrating lymphocytes are a major predictor for overall survival and response to immunotherapy for several malignancies. However, while tumour-infiltrating CD8 T cells have been extensively studied, little is known about the role of the humoral immune system within the tumour microenvironment (TME). Here we show that plasma cells are present in the TME and actively secrete human papillomavirus (HPV)-specific IgG antibodies in HPV-positive head and neck squamous cell carcinoma patients. Compared to circulating memory B cells, plasma cells in the TME were enriched for HPV-reactivity with little bystander recruitment of influenza-specific cells. HPV-specific plasma cells in the TME correlated with the antibody titres in peripheral blood and produced antibodies with a high degree of somatic hypermutation directed against HPV E2, E6 and E7 antigens. A striking proportion of HPV-specific antibodies produced in situ were directed against E2, which might thus be a promising target for immunotherapies in HPV-associated cancers. Overall, we show that antigen-specific activated and germinal centre B cells as well as plasma cells can be found in the TME, with plasma cells producing antibodies specific for tumour-associated antigens in situ. These findings provide a better understanding of humoral immune responses in human cancer and suggest that tumour-infiltrating B cells could be harnessed for the development of novel therapeutic agents.

2020-07-20 | GSE149327 | GEO

Systemic LRG1 expression in melanoma is associated with disease progression and recurrence

Project description:Treatment of late-stage melanoma patients with immune checkpoint blockade (ICB) is currently one of the most effective standard therapies. The response rates upon neoadjuvant ICB in stage III melanoma are higher as compared to stage IV disease. Given that successful ICB depends on systemic immune response, we hypothesized that systemic immune suppression might be a mechanism responsible for lower response rates in late-stage disease, and also potentially with disease recurrence in early-stage disease.

2024-01-09 | PXD040399 | Pride

RNA-Seq comparison between BrafCA;Cdkn2af/f control and BrafCA;Cdkn2af/f; Arf6Q67L mouse tumors

Project description:We analyzed transcriptomes from BRAFV600E/CDKN2ANull + ARF6Q67L mouse melanoma tumors to identify novel ARF6-regulated target genes and pathways. A unique gene expression signature in the ARF6Q67L tumors included upregulated genes related to known ARF6-dependent cell functions in trafficking, cell adhesion, motility, providing an internal positive control that helps to validate the utility of RNA sequencing as a discovery tool for ARF6. Interestingly, mTOR signaling components were upregulated in ARF6Q67L tumors, including Pik3r1, which encodes the p85 regulatory subunit of PI3 kinase (PI3K). This finding is provocative because the PI3K pathway is strongly linked to melanoma disease progression and because our ARF6Q67L mice showed a comparable metastatic phenotype to mice with PTEN loss. Transcript levels of Pik3r1 were increased in ARF6Q67L tumors compared to BrafCA;Cdkn2af/f controls.

2019-07-01 | GSE129392 | GEO

Transcriptionally inactive ATF2 variant drives melanomagenesis [Seq]

Project description:Characterized by striking metastatic propensity and chemoresistance, melanoma is among the most lethal cutaneous malignancies. The transcription factor ATF2 was shown to elicit oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, a mouse model engineered to express a transcriptionally inactive form of Atf2 (Atf2?8,9) was found to be sufficient to induce nevi formation and, when crossed with BrafV600E animals, to promote melanoma development. The cross of Atf2?8,9 with BrafV600E;Pten-/- mice augmented pigmentation, tumorigenicity, and metastasis. Similar to mouse Atf2?8,9, the human ATF2 splice variant 5 enhanced growth and migration capacity of cultured melanoma and immortalized melanocytes. Induced Melan-A, CXCL9, S100A8, CCR7 expression, seen in Atf2?8,9-driven tumors associate with their enhanced pigmentation, immune infiltration and propensity to metastasize. Notably, elevated ATF2SV5 expression in melanoma specimens coincided with poor prognosis. The gain-of-function activity elicited by the truncated ATF2 form offers unexpected insight into mechanisms underlying melanoma development and progression.

2016-04-29 | GSE79917 | GEO

Transcriptionally inactive ATF2 variant drives melanomagenesis [Array]

2016-05-02 | GSE81013 | GEO

An Immunological Synapse Formation Between T Regulatory Cells and Cancer-Associated Fibroblasts Promotes Tumour Development: Secretomics

Project description:Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment (TME), serving diverse functions in tumour progression, invasion, matrix remodelling and resistance to therapy. Extensive molecular characterization revealed an increased heterogeneity in the CAF compartment and proposed an interaction between CAFs and tumour-infiltrating immune cells, which may shape tumour immune evasion. However, the precise mechanisms via which CAFs imprint on anti-tumour immunity remain poorly understood. Herein, we describe a synapse formation between α-SMA+ CAFs and regulatory T cells (Tregs) in the TME. Specifically, Foxp3+ Tregs were localized close to α-SMA+ CAFs in diverse types of tumour models as well as in biopsies from melanoma and colorectal cancer patients. Notably, α-SMA+ CAFs demonstrated the ability to phagocytose and process tumour antigens and exhibited a tolerogenic phenotype which instructed a Treg cell movement arrest with Treg cell activation and proliferation, in an antigen-specific manner. Of interest, α-SMA+ CAFs were characterized by the presence of double-membrane structures, resembling autophagosomes, in their cytoplasm, while analysis of single-cell transcriptomic data pointed autophagy and antigen processing/presentation pathways to be enriched in α-SMA-expressing CAF clusters. In a mechanistic view, conditional knockout of the autophagy pathway in α-SMA+ CAFs promoted an inflammatory re-programming of CAFs, reduced Treg cell infiltration, attenuated tumour development, and potentiated the efficacy of immune checkpoint inhibitor immunotherapy. Overall, our findings reveal an immunosuppressive mechanism operating in the TME, which entails the formation of synapses between α-SMA+ CAFs and Tregs in an autophagy-dependent fashion and raises the potential for the development of CAF-targeted therapies in cancer. Here we submit the secretome proteomic analyses.

2024-05-08 | PXD047038 | Pride

TLR2 promotes tumour proliferation in KRAS-dependant PDAC in the absence of ARF6

Project description:Metastasis is responsible for nearly 90% of all cancer-related deaths. Despite global efforts to prevent aggressive tumours, cancers such as pancreatic ductal adenocarcinoma (PDAC) are poorly diagnosed in the primary stage, resulting in lethal metastatic disease. RAS mutations are known to promote tumour spread, with mutant KRAS present in almost 90% of cases. Until recently, mutant KRAS remained untargeted and, despite the recent development of inhibitors, results show that tumour cells develop resistance. Another strategy for targeting mutant KRAS-dependent PDAC metastasis may come from targeting the downstream effectors of KRAS. One such axis, which controls tumour proliferation, invasiveness and immune evasion, is represented by ARF6-ASAP1. Here we show that targeting ARF6 results in adaptive rewiring that can restore proliferation and invasion potential over time. Using time-series RNA and ATAC sequencing approaches, we identified TLR-dependent NFκB, TNFα and hypoxia signalling as key drivers of adaptation in ARF6-depleted KRAS-dependent PDAC. Using in vitro and in vivo assays, we show that knocking down TLR2 with ARF6 significantly reduces proliferation, migration and invasion. Taken together, our data shed light on a novel co-targeting strategy with the therapeutic potential to counteract PDAC proliferation and metastasis.

2023-12-02 | GSE247513 | GEO

STUB1 is an intracellular checkpoint for interferon gamma sensing

Project description:Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNg) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNg response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models - with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNg sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.

2022-08-18 | PXD035392 | Pride

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