RNAseq on tumors isolated from CT26 tumor bearing mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE153239 | GEO | 2020/06/26
REPOSITORIES: GEO
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Project description:RNAseq on tumors isolated from CT26 tumor bearing mice
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Project description:Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, the majority of cancer patients fail to respond clinically. One potential reason is the accumulation of transforming growth factor-beta (TGFb) in the tumor microenvironment (TME). TGFb drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8+ T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGF1, TGFb2 and TGFb3, with its expression restricted in effector Tregs, cancer cells as well as platelets. Herein we demonstrate that GARP overexpression in human cancers correlates with unfavorable TME and poor clinical response to ICB, raising a possibility of GARP blockade to improve cancer immunotherapy. However, it is unclear if targeting GARP in the TME is feasible without affecting platelets. We report an anti-human GARP antibody (named PIIO-1) specific for its ligand-interacting domain, effectively blocking activation of latent TGFb1. PIIO-1 lacks recognition of GARP-TGF complex on platelets. Using human GARP knock-in mice, we demonstrate that PIIO-1 does not cause thrombocytopenia, and is preferentially distributed in the TME and effective for treating both GARP+ and GARP- cancers, alone or in combination with anti-PD-1 antibody. PIIO-1 treatment reduces canonical TGFb signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8+ T cell migration into the TME in a CXCR3-dependent manner. Collectively, we conclude that GARP contributes to multiple aspects of immune resistance in cancer; anti-GARP antibody PIIO-1 is an efficacious and safe strategy to overcome ICB resistance, therefore warranting clinical development.
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Project description:Immune checkpoint blockade (ICB) with PD1 or PDL1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of the patients respond and sustained remissions are rare. Both chemotherapy and anti-angiogenic drugs may improve tumor response to ICB in mouse models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/p53null NSCLC, including a mismatch repair-deficient variant (KrasG12D/p53null/Msh2null) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, anti-angiogenic therapy, and chemotherapy. Anti-angiogenic blockade of VEGFA and angiopoietin-2 markedly slowed progression of established tumors but, contrary to findings in other mouse cancer models, addition of a PD1 or PDL1 antibody was not beneficial and even accelerated progression of some of the tumors. We found that anti-angiogenic treatment facilitated tumor infiltration by PD1+ regulatory T cells (T-regs), which were more efficiently targeted by the PD1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of bone-marrow origin, which are CSF1R-dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establishing a TGFB-rich tumor microenvironment that supported PD1+ T-regs. Dual TAM targeting with a combination of cisplatin and a CSF1R inhibitor fully abated T-regs, redirected the PD1 antibody to CD8+ T cells, and improved the efficacy of anti-angiogenic immunotherapy, achieving regression of the majority of the tumors.
2021-08-15 | GSE169195 | GEO
Project description:T cell infiltration is essential for immune checkpoint inhibitors to be effective in treating solid cancers. Through a bioinformatic pipeline, we identified a target gene SUN1 that might relate to modulating immune cell infiltration and immune response. Thus, we generated one Sun1_knockout CT26 cell line (Sun1_KO) and two control CT26 cell lines (Sun1_Control) using CRISPR-Cas9. By performing RNA-seq on cultured cells, tumors grown in syngeneic model, and purified tumor cells from tumors grown in syngeneic model, we set out to understand how mouse Sun1 can affect immune-related pathways and immune cell infiltration and anti-PD1 efficacy in BALB/c mice.
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Project description:Triptolide, the main active ingredient in Tripterygium wilfordii Hook. f. (Celastraceae), has shown promising effects against a variety of tumors. However, the molecular pharmacological mechanisms explaining the action of triptolide remain unknown. In this study, the CT26 colon tumor cell line was inoculated subcutaneously into BALB/c mice, and plasma samples were subjected to 1H NMR metabolomics analysis. The metabolic signature identified five metabolites whose levels were lower and 15 whose levels were higher in CT26 tumor-bearing mice than in normal control mice. Triptolide treatment significantly reversed the levels of nine of these metabolites, including isoleucine, glutamine, methionine, proline, 3-hydroxybutyric acid, 2-hydroxyisovalerate, 2-hydroxyisobutyrate, and low-density lipoprotein/very low-density lipoprotein. Based on the identities of these potential biomarkers, we conclude that the antitumor mechanism of triptolide might rely on correcting perturbations in branched-chain amino acid metabolism, serine/glycine/methionine biosynthesis, and ketone bodies metabolism.
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Project description:Only a subgroup of triple-negative breast cancer (TNBC) responds to immune checkpoint inhibitors (ICI). To better understand lack of response to ICI, we analyzed 681 TNBCs for spatial immune cell contextures in relation to clinical outcomes as well as pathways of T-cell evasion. Excluded, ignored and inflamed phenotypes were captured by a gene classifier that predicts prognosis of various cancers as well as anti-PD1 response of metastatic TNBC patients in a phase II trial. The excluded phenotype, which was associated with resistance to anti-PD1, demonstrated deposits of collagen-10, enhanced glycolysis, and activation of TGFb/VEGF pathways; the ignored phenotype, also associated with resistance to anti-PD1, showed either high density of CD163+ myeloid cells or activation of WNT/PPARg pathways; whereas the inflamed phenotype, which was associated with response to anti-PD1, revealed necrosis, high density of CLEC9A+ dendritic cells, high TCR clonality independent of neo-antigens, and enhanced expression of T-cell co-inhibitory receptors.
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Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
2023-06-16 | MSV000092193 | MassIVE