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Macrophages foster anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

ABSTRACT: Macrophages foster anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

PROVIDER: PRJNA1208954 | ENA |

REPOSITORIES: ENA

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Macrophages foster anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

Project description:Tumor-associated macrophages (TAMs) dynamically influence anti-tumor immunity. Understanding TAM function and plasticity is therefore critical to design immunotherapies. By combining syngeneic models of colorectal and pancreatic cancer with cell type-specific deletion of Zeb1, a key driver of epithelial-to-mesenchymal transition that is expressed in subsets of TAMs, we discovered that ZEB1 is an intrinsic regulator of TAM-controlled T cell trafficking. ZEB1 supports secretion of a subset of chemokines via the constitutive pathway, including CCL2 and CCL22, by promoting their biosynthesis, vesicular transport and release. This elevates CCL2 and CCL22-driven cytotoxic T cell (CTL) recruitment in vitro and fosters immunosurveillance by CTLs in tumors and metastases as well in an organotypic model for adoptive cell transfer. Our study identifies ZEB1 in TAMs as a facilitator of anti-tumor immunity, suggests a window of opportunity for cytokine-guided CTL tropism and reinforces the importance of onco-immunological context, particularly in the design of macrophage-/ cytokine-depleting strategies.

2025-05-07 | GSE286348 | GEO

Exosomal OX40L elicits positive T cell co-stimulation and promotes anti-tumor immunity through engagement of cytotoxic T lymphocytes

Project description:Exosomes play a role in immune regulation associated with cancer and other diseases. We generated exosomes that harbor the ligand of the co-stimulatory OX40 pathway, and demonstrated abundant levels of OX40L on the surface of exosomes, without inducing morphological and molecular alterations. Functionally, exosomal OX40L efficiently elicits positive co-stimulation of both human and murine T cells. The systemic administration of exosomal OX40L promotes anti-tumor immunity in an orthotopic melanoma mouse model, and the depletion of T cell subsets revealed that exosomal OX40L acts through CD8+ T cells. Mechanistically, exosomal OX40L enhances the proportion and the levels of cytotoxic markers in tumor-infiltrating CD8+ T lymphocytes. Taken together, using the OX40 pathway as proxy, we provide proof-of-principle evidence that the presence of positive co-stimulatory molecules on exosomes can functionally engage T cells to elicit anti-tumor immunity, paving the way to understand the biology of exosome-mediate T cell signaling and for further developing exosome-based reagents that engage T cell co-stimulation.

2025-02-10 | PXD031404 | Pride

PRMT1 suppresses anti-tumor immunity

Project description:PRMT1 suppresses anti-tumor immunity

| PRJNA840921 | ENA

Type-I interferon priming signal balances anti-bacterial and anti-tumor trained immunity in alveolar macrophages [ATAC-seq]

Project description:Tissue-resident macrophages may be trained to confer enhanced response to heterologous re-stimulation, and thus foster versatile trained immunity (TI) against both infections and tumors. However, key priming signals that contribute to such functional versatility in trained macrophages remain not fully understood. Here we show that influenza A virus (IAV) infection in mice induces lasting transcriptional imprints of acute type-I interferon (IFN-I) signaling in lung-resident alveolar macrophages (AMs) that confer balanced anti-bacterial and anti-tumor TI responses. In both IAV-infected mice and an ex vivo cytokine-mediated training system, IFN-I signaling is found to be critical to developing anti-tumor TI functions, although it limits anti-bacterial TI functions in AMs. Moreover, human AMs carrying transcriptional imprints of IFN-I signaling are associated with anti-tumor immunity and immune activation in lung cancer tissues. Our findings highlight IFN-I as a key priming signal required to developing versatile TI functions in AMs with balanced anti-bacterial and anti-tumor potential.

2025-05-07 | GSE295482 | GEO

Type-I interferon priming signal balances anti-bacterial and anti-tumor trained immunity in alveolar macrophages [RNA-seq]

2025-05-07 | GSE295483 | GEO

Ptpn2 regulates the generation of cytotoxic Tim-3+ CD8+ T cells and restrains anti-tumor immunity

Project description:Ptpn2 regulates the generation of cytotoxic Tim-3+ CD8+ T cells and restrains anti-tumor immunity

| PRJNA488638 | ENA

TGF-β and CIS inhibition overcomes NK cell suppression to restore anti-tumor immunity

Project description:Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8 T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK cell anti-tumor function is dependent on the cytokine interleukin (IL)-15. Ablation of the IL-15 signaling inhibitor CIS (Cish) enhances NK cell anti-tumor immunity by increasing NK cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK cell fitness via the production of immunosuppressive TGF-b, a suppression which occurs even in the presence of high IL-15 signaling. Here, we identified an unexpected interaction between CIS and the TGF-b signaling pathway in NK cells. Independently, Cish- and Tgfbr2- deficient NK cells are both hyper-responsive to IL-15 and hypo-responsive to TGF-b, with dramatically enhanced anti-tumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anti-cancer immunity.

2022-04-11 | GSE200134 | GEO

FTO degradation targeting enhances anti-tumor immunity

Project description:FTO degradation targeting enhances anti-tumor immunity

| PRJNA1053378 | ENA

6ThiodG induces anti-tumor immunity in SCLC

Project description:6ThiodG induces anti-tumor immunity in SCLC

| PRJNA933593 | ENA

Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity

Project description:Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity

| PRJNA955168 | ENA