Combination LIGHT overexpression and checkpoint blockade disrupts the tumor immune environment eradicating colorectal liver metastases
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PROVIDER: PRJNA1061481 | ENA |
REPOSITORIES: ENA
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Project description:Liver metastases contribute to resistance to cancer immunotherapy across tumor types and thus disrupting the immunosuppressive microenvironment of liver metastases is a therapeutic challenge. The expression of LIGHT, an immunostimulatory cytokine, can increase tumor-infiltrating T cells into colorectal cancer liver metastases and form tertiary lymphoid structures. We investigated the effect of combined anti-CTLA-4 and LIGHT expression in a mouse model of liver metastasis, demonstrating synergistic effects on tumor control, Treg-mediated suppression, and T cell activation, proliferation, and exhaustion. While intratumoral LIGHT or anti-CTLA-4 alone induced tumor-associated macrophages (TAM), only the combination led to a decrease in TAM and MDSC populations and activation of dendritic cells. The combination of LIGHT and anti-CTLA-4 represents a strategy of overcoming immunosuppression in colorectal cancer as well as other microsatellite stable tumors in which liver metastases drive resistance to immunotherapy.
2025-08-29 | GSE252597 | GEO
Project description:Bone metastases remain incurable and respond poorly to immune checkpoint blockade (ICB) therapy. The impact of neutrophil maturation in cancer remains largely unknown, especially in refractory tumors including bone metastases. Here, we observed the predominance of immature neutrophils in the bone metastasis microenvironment of both mouse models and cancer patients. DKK1 induces the immature-like functional state in neutrophils, which exert robust immunosuppressive capabilities to inhibit anti-tumor response of CD8+ T cells. Mechanistically, driven by the DKK1-CKAP4-STAT6 signaling, Chil3 expression is identified and required for the immune suppression mediated by immature neutrophils in bone metastases. Moreover, using multiple syngeneic and human immune system (HIS) mouse models, we found that DKK1 blockade efficiently allows neutrophil maturation to improve the immune microenvironment, controls tumor progression, and enhances ICB therapy response in bone metastases. Thus, our findings uncover an essential role for immature neutrophils in cancer, especially in bone metastases, and propose a potential strategy modulating neutrophils to improve cancer immunotherapy.
2025-06-01 | GSE295537 | GEO
Project description:Bone metastases remain incurable and respond poorly to immune checkpoint blockade (ICB) therapy. The impact of neutrophil maturation in cancer remains largely unknown, especially in refractory tumors including bone metastases. Here, we observed the predominance of immature neutrophils in the bone metastasis microenvironment of both mouse models and cancer patients. DKK1 induces the immature-like functional state in neutrophils, which exert robust immunosuppressive capabilities to inhibit anti-tumor response of CD8+ T cells. Mechanistically, driven by the DKK1-CKAP4-STAT6 signaling, Chil3 expression is identified and required for the immune suppression mediated by immature neutrophils in bone metastases. Moreover, using multiple syngeneic and human immune system (HIS) mouse models, we found that DKK1 blockade efficiently allows neutrophil maturation to improve the immune microenvironment, controls tumor progression, and enhances ICB therapy response in bone metastases. Thus, our findings uncover an essential role for immature neutrophils in cancer, especially in bone metastases, and propose a potential strategy modulating neutrophils to improve cancer immunotherapy.
2025-06-01 | GSE295533 | GEO
Project description:Characterization of CNS Metastases
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Project description:Characterization of CNS Metastases
| PRJNA726829 | ENA
Project description:An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and protein expression and activation, quantitatively analyzed by molecular inversion probe arrays, microarrays and reverse phase protein array (RPPA) were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. Seventy-two samples from 52 brain (except for patient 01, who had a spinal cord metastasis) and extracranial metastases of melanoma were analyzed. Available biological replicates (different parts of the same tumor) were included.
2014-05-08 | E-GEOD-50493 | biostudies-arrayexpress
Project description:Approximately half of women diagnosed with advanced triple negative breast cancer (TNBC) will develop brain metastases, of which the majority will have uncontrolled extracranial disease. While local therapies to treat brain metastases are standardly prescribed, survival remains less than 6 months. This phase II, multi-center trial evaluated efficacy of irinotecan and iniparib, anti-cancer agents with activity in TNBC and known to cross the blood brain barrier, among 34 patients with new or progressive TNBC brain metastases. While time to progression was short (2.1 months), 27% of patients experienced intracranial clinical benefit and therapy was well-tolerated. Correlative studies illustrate partial response was associated with germline BRCA mutation status and high tumor expression of proliferation genes and signatures. To our knowledge, this is the first study showing feasibility of enrolling patients with progressive TNBC brain metastases to a systemic therapy and lays the groundwork for future studies to treat this devastating disease.
2014-12-31 | GSE51280 | GEO
Project description:An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and protein expression and activation, quantitatively analyzed by molecular inversion probe arrays, microarrays and reverse phase protein array (RPPA) were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors.
2014-05-08 | GSE50493 | GEO
Project description:Jailkhani N, Clauser KR, Mak H, Rickelt S, Tian C, Whittaker CA, Tanabe KK, Purdy SR, Carr SA, and Hynes RO.2022.
Metastases are hard to detect and treat, and cause most cancer-related deaths. The relative lack of therapies targeting metastases represents a major unmet clinical need. The extracellular matrix or ECM forms a major component of the tumor microenvironment in both primary and metastatic tumors and certain ECM proteins can be selectively and abundantly expressed in such tumors. We propose that nanobodies against ECM proteins that show selective abundance in metastases can be used as vehicles for delivery of imaging and therapeutic cargoes. To gain a deeper understanding of the microenvironment of human metastases, we describe here an LC-MS/MS-based ECM signature shared by human TNBC and CRC metastases to different organs and provide evidence that this conserved set of ECM proteins is selectively elevated in other tumors. We also describe phage-display libraries of nanobodies raised against ECM-enriched preparations from human metastases from TNBC and CRC. As proof of concept, we developed selective and specific, high-affinity nanobodies against an example signature protein, Tenascin-C (TNC), known to be abundant in many tumor types and to play a role in metastases. We report that TNC is abundantly expressed in patient metastases and widely expressed across diverse metastatic sites originating from several primary tumor types. Using immuno-PET/CT we showed that anti-TNC nanobodies bind TNBC tumors and metastases with excellent specificity. We propose that such generic anti-tumor nanobodies are promising cancer-agnostic, in vivo tools for the delivery of therapeutics to tumor and metastatic ECM.
2022-03-28 | MSV000089136 | MassIVE
Project description:This study investigated how the depletion of natural killer (NK) cells in mice treated with a combined PD-1/CTLA-4 blockade affects the molecular profiles of intracranial tumors in a two-site B16-OVA melanoma brain metastases model. This model contains concomitant intracranial and extracranial tumors, to mimic the presence of extracranial metastases in melanoma patients with brain metastases, and intracranial responses to the combined PD-1/CTLA-4 blockade that are observed in the clinic can be reproduced in this model.
2024-08-29 | GSE264376 | GEO