CaMKK2 in myeloid cells is a key regulator of the immune suppressive microenvironment in breast cancer
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ABSTRACT:
PROVIDER: PRJNA416369 | ENA |
REPOSITORIES: ENA
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Project description:Tumor-associated myeloid cells play a pivotal role in the regulation of processes that control tumor growth and metastasis, and their accumulation in tumors is an established negative prognostic factor in breast cancer. Here, we show that inhibition of calcium/calmodulin-dependentkinase kinase 2 (CaMKK2) expression within myeloid cells inhibits tumor growth in mouse models of mammary cancer. This activity is associated with the accumulation of macrophages within the tumor microenvironment that express high levels of the major histocompatibility molecule class II molecule I-A (MHC II I-A), and granzyme positive CD8+T-cells. Treatment with specific CaMKK2 inhibitors block tumor growth, in a CD8+ T-cell dependent manner, and facilitates favorable reprogramming of the immune cell microenvironment. CaMKK2 protein expression was highest in the most aggressive subtypes of human breast cancer and, in the most malignant tumors, both tumor cells and tumor-associated macrophages express high levels of this enzyme. In aggregate, these findings implicate CaMKK2 as a macrophage-selective immune checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.
2019-06-16 | GSE106357 | GEO
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Project description:We analyzed 40,799 single cells from nine samples and found that in EGFR-mutant LUAD, tumor cells generated an immunosuppressive microenvironment by releasing cytokines to attract suppressive immune cells such as myeloid-derived suppressor cells (MDSCs) directly or indirectly by interacting with macrophages, dendritic cells, or other cell types. By contrast, EGFR wild-type LUAD had a greater ability to recruit immunocompetent T cells such as TRMs and Th1 cells, thus driving a proinflammatory microenvironment.
2022-02-09 | GSE171145 | GEO
Project description:The tumor microenvironment in brain metastases is characterized by high myeloid cell content with immune-suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T cell-directed therapies fail to elicit effective anti-tumor immune responses. Here we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastases. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune-suppressive environment to counteract re-activated T cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune-suppression and regulating T cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.
2021-02-12 | GSE164049 | GEO
Project description:Recent studies have uncovered that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 in various myeloid malignancies and aberrant hematopoietic stem cell (HSC) self-renewal/differentiation in mice with hematopoietic tissue specific loss of Tet2 have been reported, indicating that TET2 is a master regulator of normal and malignant hematopoiesis. Despite a functional link between AID and TET in epigenetic gene regulation, the role of AID loss in normal hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and contraction in erythroid progenitors resulting in pathologic anemia possibly due to dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage specific transcription factors. Consistent with data in the murine context, silencing of AID skews differentiation towards myelomonocytic lineage in human BM cells. However, in contrast to Tet2, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD in myeloid leukemogenesis. Genome-wide transcription and differential methylation analysis uncover critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, and that their role is non-redundant in regulating HSC self-renewal and in myeloid transformation.
2017-10-01 | GSE88842 | GEO
Project description:Recent studies have uncovered that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 in various myeloid malignancies and aberrant hematopoietic stem cell (HSC) self-renewal/differentiation in mice with hematopoietic tissue specific loss of Tet2 have been reported, indicating that TET2 is a master regulator of normal and malignant hematopoiesis. Despite a functional link between AID and TET in epigenetic gene regulation, the role of AID loss in normal hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and contraction in erythroid progenitors resulting in pathologic anemia possibly due to dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage specific transcription factors. Consistent with data in the murine context, silencing of AID skews differentiation towards myelomonocytic lineage in human BM cells. However, in contrast to Tet2, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD in myeloid leukemogenesis. Genome-wide transcription and differential methylation analysis uncover critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, and that their role is non-redundant in regulating HSC self-renewal and in myeloid transformation.
2017-10-01 | GSE88841 | GEO
Project description:Immune suppressive landscape in a human esophageal squamous cell carcinoma microenvironment
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Project description:Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in murine hematopoietic stem/progenitor cells
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Project description:Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme - histone 3 lysine 27 demethylase (KDM6B) in intra-tumoral immune-suppressive myeloid cell subsets. Importantly, myeloid-cell specific Kdm6b deletion enhanced pro-inflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies elucidated that the absence of Kdm6b enhances antigen-presentation, interferon response and phagocytosis in myeloid cells by inhibiting mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b deleted myeloid cells and enhanced anti-PD1 efficacy. Thus, this study identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target to improve response to ICT.
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Project description:Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mon) and monocytic myeloid-derived suppressor cells (M-MDSC). Macrophages differentiated from M-MDSC, but not from Mon were immune suppressive with genomic profile matching that of M-MDSC. Immune suppressive activity of M-MDSC derived macrophages was dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promoted M2 polarization of macrophages. Tissue resident and Mon derived macrophages lacked expression of this protein. S100A9 dependent immune suppressive activity of macrophage was mediated via transcription factor CEBP/β. The presence of S100A9 positive macrophages in tumor tissues was associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study revealed the pathway of the development of immune suppressive macrophages and suggested approach to their selective targeting.
2020-12-14 | GSE162353 | GEO