Tumor-derived RAC1A159V mutation promotes an immunosuppressive tumor microenvironment that represses response to immune checkpoint inhibitor [RNA-Seq]
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PROVIDER: PRJNA1268780 | ENA |
REPOSITORIES: ENA
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Project description:Tumor-derived RAC1A159V mutation promotes an immunosuppressive tumor microenvironment that represses response to immune checkpoint inhibitor [scRNA-seq]
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Project description:Immune checkpoint inhibitors that activate cytotoxic T lymphocytes to kill cancer cells have seen great success in therapies against various tumor types. However, the overall response rate in patients remains unacceptable at ~15%. RAC1, a member of Rho GTPase family, regulates multiple cellular processes in cancer, including vesicle trafficking, glycolysis, and exocytosis/endocytosis, which may contribute to tumor immune microenvironment modulation. RAC1A159V is a hotspot mutation found in several cancer types including colon cancer and is associated with poor prognosis. In this study, we have generated MC38 RAC1A159V cells by using CRISPR/Cas9 and confirmed that RAC1A159V results in upregulated RAC1 activity and downstream PAK1 and mTOR signaling. We have found the RAC1A159V tumors grow at a similar rate as RAC1WT tumors in immunodeficient NSG mice but faster than RAC1WT tumors in syngeneic immunoproficient mice, and the RAC1A159V tumors are highly resistant to anti-PD1 treatment. Flow cytometry and scRNA-seq analyses reveal that RAC1A159V cells form “cold” tumors with an immunosuppressive microenvironment and suppressed tumor-immune cell interactions. Mechanistically, we show RAC1A159V upregulates glycosphingolipid biosynthesis to activate mTORC1 signaling in tumor cells, which in turn increases glycolysis, impairs key chemokine production, and decreases IFNGR1 expression of the tumor cells. mTORC1 inhibition re-sensitizes the RAC1A159V tumors to anti-PD1 treatment by reversing effects by RAC1A159V mutation on tumor cell glycolysis, chemokine production, and IFNGR1 expression. Our results demonstrate that RAC1A159V in tumors drives immune evasion via mTOR mediated glycolysis, chemotaxis, and IFN-γ response, and further suggest an approach of combining targeting of RAC1-mTOR signaling with immune checkpoint inhibitors for the treatment of immune-cold RAC1A159V tumors.
2025-09-03 | GSE298274 | GEO
Project description:Immune checkpoint inhibitors that activate cytotoxic T lymphocytes to kill cancer cells have seen great success in therapies against various tumor types. However, the overall response rate in patients remains unacceptable at ~15%. RAC1, a member of Rho GTPase family, regulates multiple cellular processes in cancer, including vesicle trafficking, glycolysis, and exocytosis/endocytosis, which may contribute to tumor immune microenvironment modulation. RAC1A159V is a hotspot mutation found in several cancer types including colon cancer and is associated with poor prognosis. In this study, we have generated MC38 RAC1A159V cells by using CRISPR/Cas9 and confirmed that RAC1A159V results in upregulated RAC1 activity and downstream PAK1 and mTOR signaling. We have found the RAC1A159V tumors grow at a similar rate as RAC1WT tumors in immunodeficient NSG mice but faster than RAC1WT tumors in syngeneic immunoproficient mice, and the RAC1A159V tumors are highly resistant to anti-PD1 treatment. Flow cytometry and scRNA-seq analyses reveal that RAC1A159V cells form “cold” tumors with an immunosuppressive microenvironment and suppressed tumor-immune cell interactions. Mechanistically, we show RAC1A159V upregulates glycosphingolipid biosynthesis to activate mTORC1 signaling in tumor cells, which in turn increases glycolysis, impairs key chemokine production, and decreases IFNGR1 expression of the tumor cells. mTORC1 inhibition re-sensitizes the RAC1A159V tumors to anti-PD1 treatment by reversing effects by RAC1A159V mutation on tumor cell glycolysis, chemokine production, and IFNGR1 expression. Our results demonstrate that RAC1A159V in tumors drives immune evasion via mTOR mediated glycolysis, chemotaxis, and IFN-γ response, and further suggest an approach of combining targeting of RAC1-mTOR signaling with immune checkpoint inhibitors for the treatment of immune-cold RAC1A159V tumors.
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Project description:In this study, we utilized spatial transcriptome analysis, genomic copy number variation mutation profiling, and single-cell sequencing to identify an abnormal overexpression of TNK2, which is inversely correlated with PDAC prognosis and the development of an immune-suppressive microenvironment. Previous research has hinted at TNK2's role in tumor progression and its correlation with patient survival in various cancers, yet its involvement in the PDAC immune microenvironment and resistance to immunotherapy remains unexplored. Our findings reveal that TNK2 overexpression influences the formation of an immunosuppressive microenvironment, as demonstrated by cell communication analysis and immune landscape profiling. Additionally, TNK2 phosphorylates and activates STAT5a at the Y694 site, resulting in the upregulation of immune checkpoint HVEM and the exhaustion of CD8+ T cells. Treatment with AIM100, which disrupts the TNK2-STAT5a-HVEM regulatory axis, markedly mitigates the immunosuppressive microenvironment and enhances sensitivity to PD-1 inhibitors and AG chemotherapy.
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Project description:Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy-number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously-published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for validation of discovered subtypes and to add spatial context. Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T-cells, and LAMP3+ dendritic cells. Using cell-cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T-cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche.
2025-07-15 | GSE299025 | GEO
Project description:Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy-number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously-published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for validation of discovered subtypes and to add spatial context. Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T-cells, and LAMP3+ dendritic cells. Using cell-cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T-cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche.
2025-07-15 | GSE299023 | GEO
Project description:Tumors arise and grow despite anti-cancer immune responses. These responses can be stimulated by immunotherapies such as immune checkpoint inhibitors (e.g. anti-PD1 antibodies) and chimeric antigen receptors (CAR). Efficacy of these agents in solid tumors including colorectal cancers (CRC) is limited by immunosuppressive tumor microenvironment (TME) that prevents killing of malignant cells by cytotoxic T lymphocytes (CTL). Understanding the nature of TME-generated immunosuppression is of paramount importance. Here we report that TME elicited immunosuppression via eliminating activated CTL; this elimination required TME stress-induced downregulation of the IFNAR1 chain of type I interferon (IFN) receptor and attenuation of its signaling. Downregulation of IFNAR1 was observed in human colorectal cancers (CRC) and in mouse CRC models where it was required for efficient tumor development and progression. Stabilization of IFNAR1 on CTL improved their survival and increased anti- tumor activities of CAR T cells and PD1 inhibitors thereby providing a rationale for targeting IFNAR1 degradation for immunotherapies optimization. Two genotypes of mice were examined either 9 or 21 days post injection of MC38 colon cancer cells or MC38mRFP cells, respectively. 2-3 replicate mice were analyzed on separate arrays for each condition. 6 conditions in total were analyzed.
2016-01-15 | E-GEOD-76889 | biostudies-arrayexpress
Project description:CD74 regulates the tumor immunosuppressive microenvironment in triple-negative brest cancer
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