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Immunosuppressive crosstalk between tumour cells, myeloid cells and T cells in an anti-PD-1 plus anti-CTLA-4 therapy resistant mouse ccRCC model [RNA-seq]

ABSTRACT: Many patients respond poorly or develop resistance to immune checkpoint therapies for metastatic clear cell renal cell carcinoma (ccRCC). Here we demonstrate that ccRCCs in the Vhl/Trp53/Rb1 mutant autochthonous mouse model are resistant to anti-PD-1 plus anti-CTLA-4 therapy, providing a model of checkpoint therapy resistance. In vivo checkpoint therapy allowed isolated T cells to recognise cultured ccRCC cells, implicating the tumour microenvironment in suppression of T cell activation. Single cell RNA-seq identified putative immunosuppressive PMN-MDSC, M-MDSC and TAM populations that show similar features to myeloid cells in the microenvironment of human ccRCC. Conditioned medium of ccRCC cell lines attracted bone marrow-derived macrophages in a MIF-dependent manner and induced the mis-differentiation of bone marrow cells to M-MDSC and TAM2-like phenotypes. These cells suppressed the viability and proliferation of activated CD8+ T cells. These analyses identify new candidate cellular and molecular barriers to effective immune checkpoint therapy. We validate this concept by showing that GALECTIN-3 is the predominant checkpoint ligand expressed by ccRCC cells and myeloid cells and that anti-LAG-3 treatment increases T cell infiltration in this model.

ORGANISM(S): Mus musculus

PROVIDER: GSE259359 | GEO | 2025/02/27

REPOSITORIES: GEO

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Immunosuppressive crosstalk between tumour, myeloid and T cells in an anti-PD-1 plus anti-CTLA-4 therapy resistant mouse ccRCC model [scRNA-seq]

Project description:Many patients respond poorly or develop resistance to immune checkpoint therapies for metastatic clear cell renal cell carcinoma (ccRCC). Here we demonstrate that ccRCCs in the Vhl/Trp53/Rb1 mutant autochthonous mouse model are resistant to anti-PD-1 plus anti-CTLA-4 therapy, providing a model of checkpoint therapy resistance. In vivo checkpoint therapy allowed isolated T cells to recognise cultured ccRCC cells, implicating the tumour microenvironment in suppression of T cell activation. Single cell RNA-seq identified putative immunosuppressive PMN-MDSC, M-MDSC and TAM populations that show similar features to myeloid cells in the microenvironment of human ccRCC. Conditioned medium of ccRCC cell lines attracted bone marrow-derived macrophages in a MIF-dependent manner and induced the mis-differentiation of bone marrow cells to M-MDSC and TAM2-like phenotypes. These cells suppressed the viability and proliferation of activated CD8+ T cells. These analyses identify new candidate cellular and molecular barriers to effective immune checkpoint therapy. We validate this concept by showing that GALECTIN-3 is the predominant checkpoint ligand expressed by ccRCC cells and myeloid cells and that anti-LAG-3 treatment increases T cell infiltration in this model.

2025-02-27 | GSE259361 | GEO

TIE-2 expressing monocytic myeloid-derived suppressor cells are involved in resistance to anti-PD-1 mediates by angiopoietin 2 in melanoma patients

Project description:Immunotherapy using immune checkpoint inhibitors (ICI) has revolutionized the management of melanoma. Although the anti-PD-1 antibodies induce a 40% objective response rate (ORR) in advanced melanoma patients, the majority of patients have a primary resistance or develop a secondary resistance (Robert et al. 2015). Many resistance mechanisms have been described including the loss of the expression of class I MHC, the alteration of antigen presentation, JAK/STAT pathway mutation, or the overexpression of another inhibitory molecule (LAG-3, TIM-3, …). It was also known that immunosuppressive cells such as myeloid-derived Suppressor Cells (MDSC) can negatively impact the efficacy of anti-PD-1 therapy (Limagne et al. 2019). MDSCs are a group of immunosuppressive heterogenous cells found in many cancers that inhibit antitumor T cell functions by several mechanisms. We previously described in lung cancer a novel subpopulation of monocytic MDSC (M-MDSC) overexpressing TIE-2 that mediate inhibition of antitumor T cell responses after angiopoietin-2 (ANGPT2) exposure. Furthermore, we found, that a high level of circulating TIE-2+ M-MDSC and ANGPT2 in melanoma patients is associated with a poor prognosis by inhibiting anti-melanoma T-cell responses (Marguier et al. 2022).TIE-2 is a tyrosine kinase with immunoglobulin and EGF homology domains. This receptor was mainly expressed by endothelial cells but can be expressed by tumor cells and some immune cells such as monocytes. TIE-2 binds to the pro-angiogenic factor ANGPT2 which is involved in tumor neo-angiogenesis. Recent findings in melanoma also showed the implication of ANGPT2 in resistance to anti-PD-1 therapy by promoting the exclusion of T cells (Park et al. 2023). Thus, we assumed that TIE-2+ M-MDSC would be involved in this negative impact of ANGPT2 on anti-PD-1 therapy.

2025-04-08 | GSE288083 | GEO

RNA sequencing of blood-brain barrier (BBB) microvessels from mice with orthotopic GBM showing the benefit of triple therapy combining anti-immune checkpoint therapy with dual-anti angiogenic therapy.

Project description:Glioblastoma multiforme (GBM) is a non T cell-inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T cell cytotoxicity. The alleviation of immunosuppression might be a prerequisite for succesful immune checkpoint therapy in GBM. We here combine anti-angiogenic and immune checkpoint therapy and demonstrate improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of vascular endothelial growth factor (VEGF), Angiopoietin-2 (Ang-2) and programmed cell death protein-1 (PD-1) significantly extended survival compared to vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of cytotoxic T-lymphocytes that inversely correlated with myeloid-derived suppressor and regulatory T cells. Furthermore, transcriptomic analysis of GBM microvessels indicates a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce anti-tumor immunity through a normalized vasculature.

2021-03-01 | GSE130324 | GEO

PBAF loss leads to DNA damage induced inflammatory signalling through defective G2/M checkpoint maintenance

Project description:PBRM1 is a subunit of the PBAF (SWI/SNF) chromatin remodelling complex that is mutated in approximately 40% of clear cell renal cell carcinomas (ccRCC). PBRM1 loss has been implicated in the response to immune checkpoint inhibitor (ICI) therapy in ccRCC. However, it is unclear how PBRM1 influences this. DNA damage-induced inflammatory signalling is an important factor determining ICI therapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. Here, we show that PBRM1 is required for p53-dependent maintenance of the G2/M checkpoint. In its absence, p53-dependent transcriptional upregulation of p21 is delayed, leading to defective repression of DREAM complex targets and premature entry into mitosis. Consequently, DNA damage induced inflammatory signalling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in ccRCC, so PBRM1 mutational status is critical to G2/M checkpoint maintenance following DNA damage in this cancer. These findings have implications for ICI therapy responses in ccRCC.

2022-10-13 | PXD028336 | Pride

Immune Restoring (IR) CAR-T Cells Display Superior Antitumor Activity and Reverse Immunosuppressive TME in a Humanized ccRCC Orthotopic Mouse Model

Project description:Here we report a humanized clear cell renal cell carcinoma (ccRCC) orthotopic NSG-SGM3 mouse model (hccRCC-NSG-SGM3) with reconstituted human lymphocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) bearing human ccRCC skrc-59 cells under the kidney capsule. Human leukocyte antigen (HLA) matched CD34+ HSCs were used for the humanization to reduce T cell alloreactivity against skrc-59 human ccRCC cells. Tumors were collected and sorted for CD45+ tumor infiltrated leukocytes (TILs) to profile the tumor microenvironment (TME) in hccRCC-NSG-SGM3. By comparing to patient data from prospective clinical trials of the anti-PD-1 monoclonal antibody (mAb) nivolumab in advanced ccRCC, the results demonstrated that the CD45+ TILs from hccRCC-NSG-SGM3 reconstitutes most CD45+ cell types, including NK cells, dendritic cells, exhausted CD8 T cells, regulatory T cells (Tregs), that are observed in advanced ccRCC patient TME. Furthermore, Anti-carbonic anhydrase IX (CAIX) G36 immune restoring (IR) chimeric antigen receptor (CAR) T cells secreting PD-L1 targeted immune checkpoint inhibitor (ICI) mAb (G36-PDL1) exhibited superior tumor control compared to G36 CAR-T cells with anti-SARS mAb (G36-SARS) and anti-BCMA A716 CAR-T cells with anti-PD-L1 mAb (A716-PDL1). In addition, G36-PDL1 CAR-T cells restored active anti-tumor immunity at tumor site uncovered by 10X genomics single cell RNA sequencing (scRNA-seq) and single cell T cell receptor sequencing (scTCR-seq).

2024-01-25 | GSE210664 | GEO

Mesenchymal-like tumor cells and myofibroblastic cancer-associated fibroblasts are associated with progression and immunotherapy response of clear-cell renal cell carcinoma [scRNA-seq]

Project description:Immune checkpoint inhibitors (ICI) represent the cornerstone for treatment of patients with metastatic clear-cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease highlighting the need to precisely understand plasticity of cancer cells and their crosstalk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial to mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public datasets and in data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAFs), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. This data highlights the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance.

2023-06-26 | GSE210038 | GEO

Mesenchymal-like tumor cells and myofibroblastic cancer-associated fibroblasts are associated with progression and immunotherapy response of clear-cell renal cell carcinoma [spatial transcriptomics]

2023-06-26 | GSE210041 | GEO

Integrated Multi-Omics Profiling for the Identification of Markers Associated with Myeloid-Derived Suppressor Cells in Human Isogenic Cell Line Models of Neutrophils and Myeloid-Derived Suppressor Cells

Project description:This study presents an integrative analysis identifying a 26-gene signature associated with myeloid-derived suppressor cells (MDSCs) in cancer, leveraging mass spectrometry proteomics data, RNA sequencing data and external datasets from lung and head and neck cancers. The genes within this signature were found to correlate positively with MDSC infiltration and negatively with neutrophil and CD8+ T cell presence in the tumor microenvironment. Clinically, this signature showed a significant association with reduced survival rates in metastatic melanoma patients treated with PD1 inhibitors, highlighting its potential as a prognostic biomarker in cancer therapy. This study enhances our understanding of MDSCs in oncology and opens new avenues for targeted therapeutic strategies against MDSC-mediated immunosuppression in the tumor microenvironment.

2024-06-22 | PXD048934 | Pride

Sirt2 Inhibition Reprograms T Cell Metabolism to Confer Superior Anti-Tumor Immunity

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Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for β-catenin driven melanomas [transfection]

Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.

2023-10-30 | GSE155394 | GEO

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