Cancer immunotherapy via synergistic co-activation of myeloid cells [scRNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233171 | GEO | 2023/11/10
REPOSITORIES: GEO
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Project description:Myeloid cells coordinate T cell immune evasion in cancer yet are pliable and possess anti-tumor potential. Here, by co-targeting activation molecules we leverage the myeloid compartment as a therapeutic vulnerability in cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor CLEC7A and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, co-activation of CLEC7A, via systemic β-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Anti-tumor activity was dependent on a cDC1 – T cell axis but did not require classical T cell cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-derived IFNγ signaling which converged with CLEC7A activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance can be invoked by co-activation of complementary myeloid signaling pathways.
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Project description:Agonistic CD40 monoclonal antibodies have emerged as promising immunotherapeutic compounds with impressive anti-tumoral effects. However, one of the main limitations of their use in patients is the severe liver necro-hepatitis they can induce. Up to this point, no effective treatment for anti-CD40 liver toxicity that does not hinder anti-tumor efficacy has been found. In the present study , we show that anti-CD40 liver toxicity is dependent on liver macrophages and recruitment of monocytes and neutrophils. We specifically reprogrammed the phenotype of liver macrophages to anti-inflammatory erythrophagocytes by using repeated injection of anti-erythrocyte murine Ter119 (mTer119) antibody. mTer119 administration induced phagocytosis of erythrocytes by liver macrophages and their transformation to Hmoxhigh/Marcohigh/MHC-IIlow erythrophagocytes. mTer119 treatment prevented anti-CD40 induced liver toxic side-effect, with significantly reduced elevation of plasma transaminases level and area of liver necrosis on histology, while preserving the anti-tumoral efficiency of anti-CD40. Our study offers a novel targeted therapeutic approach to treat immune-related liver adverse side effects of immunotherapies.
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Project description:Agonistic CD40 monoclonal antibodies have emerged as promising immunotherapeutic compounds with impressive anti-tumoral effects. However, one of the main limitations of their use in patients is the severe liver necro-hepatitis they can induce. Up to this point, no effective treatment for anti-CD40 liver toxicity that does not hinder anti-tumor efficacy has been found. In the present study , we show that anti-CD40 liver toxicity is dependent on liver macrophages and recruitment of monocytes and neutrophils. We specifically reprogrammed the phenotype of liver macrophages to anti-inflammatory erythrophagocytes by using repeated injection of anti-erythrocyte murine Ter119 (mTer119) antibody. mTer119 administration induced phagocytosis of erythrocytes by liver macrophages and their transformation to Hmoxhigh/Marcohigh/MHC-IIlow erythrophagocytes. mTer119 treatment prevented anti-CD40 induced liver toxic side-effect, with significantly reduced elevation of plasma transaminases level and area of liver necrosis on histology, while preserving the anti-tumoral efficiency of anti-CD40. Our study offers a novel targeted therapeutic approach to treat immune-related liver adverse side effects of immunotherapies.
2022-11-09 | GSE202917 | GEO
Project description:Organism: Mus musculus Experiment type: Gene expression profiling by high throughput sequencing Summary: Pathological angiogenesis is a hallmark of cancer and therapeutic target. Vascular-endothelial growth factor-A (VEGFA) and angiopoietin-2 (ANGPT2/ANG2) sustain tumor angiogenesis and limit anti-tumor immunity. We show that combined ANGPT2 and VEGFA blockade by mono-specific antibodies (LC06 + B20) or a bi-specific antibody (A2V) provides synergistic anti-tumoral benefits in both transgenic and transplant tumor models. We further show that that combination of agonistic anti-CD40 or blocking anti-PD1 antibodies with ANGPT2/VEGFA blockade improves therapeutic response and induces pleiotropic immune mechanisms that facilitate tumor control.
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Project description:Most cancers are cold tumors characterized by a lack of effector T cells and hence unresponsive to immune checkpoint blockades, highlighting the importance of repairing the failed T cell priming in cancer immunotherapy. CD40 agonists are efficient in eliciting T cell responses and effective in converting cold tumors into hot, their clinical application, however, is limited by the very narrow window between the effective and toxic dosages. Here, we sought to reduce the effective dosage of CD40 agonists by combination therapy. We identified a CD19+CD24hiCD38lowIgDlow/- regulatory B cell (Breg) subset that is increased in tumor-bearing mice and cancer patients, and discovered that PPARδ is highly expressed in these tumor-associated Bregs and required for their proliferation and function. Inhibition of PPARδ acted synergistically with agonist anti-CD40 to enhance antitumor immunity without increasing toxicity in murine melanoma and bladder carcinoma models. Combination therapy with PPARδ inhibitor could reduce anti-CD40 dosage by over 60% to a well-tolerated level with improved or at least not compromised antitumor effects, providing a potential strategy for safely using CD40 agonists in cancer treatment. PPARδ also offers a new target for selectively blocking Breg activity while sparing immunostimulatory B cells that are known to aid antitumor immunotherapy.
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Project description:CD40-stimulating immunotherapy elicits potent anti-tumor responses, which are mainly T-cell dependent. Here, we have investigated how tumor endothelial cells respond to CD40-stimulating immunotherapy by isolating endothelial cells from B16.F10 melanoma in anti-CD40 treated or isotype treated mice followed by RNA-sequencing. Gene set enrichment analysis revealed an increase in interferon- related responses in tumor endothelial cells following anti-CD40 therapy. The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) was preferentially expressed in endothelial cells, and it was up-regulated upon anti-CD40 treatment. IDO1 expression in tumor endothelium was positively correlated to T-cell infiltration and to increased expression of IFNγ in the tumor microenvironment. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic anti-CD40 therapy with the IDO1 inhibitor epacadostat delayed tumor growth and increased survival in B16.F10 tumor-bearing mice, which was associated with increased activation of tumor-infiltrating T-cells. Hereby, we have uncovered an immunosuppressive feedback mechanism, in which tumor vessels limit the efficacy of cancer immunotherapy by up-regulating IDO1 in response to T-cell activation.
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Project description:Despite the remarkable success of immunotherapy in many types of cancer, pancreatic cancer has yet to benefit. Innate immune cells are critical players in antitumor immunosurveillance. Recent studies have revealed that innate immune populations may possess a form of memory, termed trained immunity through transcriptomic, epigenetic, and metabolic reprograming. 1Here, we show that intraperitoneal administration of yeast-derived particulate β-glucan results in 90% of that dose trafficking to the pancreas. This trafficking leads to a robust influx of newly characterized innate immune cells with an inflammatory monocyte/macrophage phenotype into the pancreas in a CCR2 dependent manner. These cells also exhibit a trained immunity phenotype upon exposure to tumor-derived factors and show enhanced phagocytosis and ROS-mediated cytotoxicity against pancreatic tumors. In orthotopic models of pancreatic cancer, mice trained with β-glucan show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with anti-PD-L1 immunotherapy. Cumulatively, these findings highlight a novel trafficking mechanism of yeast-derived particulate β-glucan that incites a phenotype of trained immunity specifically in the pancreas that can be utilized as an innovative strategy to treat pancreatic cancer.
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Project description:Goal: determine how transcriptome of immune cells within the tumor microenvironment changes as a function of CD40 agonist and/or immune checkpoint blockade (anti-PD-1 AND anti-CTLA-4; "ICB") therapy
2020-05-10 | GSE150176 | GEO
Project description:KRAS inhibitors have demonstrated exciting pre-clinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KRASG12D, p53 mutant, murine PDAC-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intra-tumoral CD8+ T cells without durable responses. scRNA-sequencing revealed an increase in inflammatory cancer associated fibroblasts (iCAFs), M2 macrophages, and a decreased dendritic cell quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor free mice with established immune memory. Our data suggests that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.
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Project description:TNF mechanistically links cytokine release and hepatotoxicity triggered by an agonist CD40 antibody, and toxicity can be suppressed by blockade of TNF without affecting anti-tumor efficacy.
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