Hypoxia PET Imaging Identifies Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy to Rescue Checkpoint Blockade Refractory Tumors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE184863 | GEO | 2021/09/28
REPOSITORIES: GEO
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Project description:Hypoxia PET Imaging Identifies Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy to Rescue Checkpoint Blockade Refractory Tumors
| PRJNA766674 | ENA
Project description:PurposeHypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated.Experimental designIn this study, we probed the tumor and its surrounding microenvironment with 18F-FMISO PET imaging to noninvasively quantify tumor hypoxia in vivo prior to and during PD-1 and CTLA-4 checkpoint blockade in preclinical models of breast and colon cancer.ResultsLongitudinal imaging identified hypoxia as an early predictive biomarker of therapeutic response (prior to anatomic changes in tumor volume) with a decreasing standard uptake value (SUV) ratio in tumors that effectively respond to therapy. PET signal correlated with ex vivo markers of tumor immune response including cytokines (IFNγ, GZMB, and TNF), damage-associated molecular pattern receptors (TLR2/4), and immune cell populations (macrophages, dendritic cells, and cytotoxic T cells). Responding tumors were marked by increased inflammation that were spatially distinct from hypoxic regions, providing a mechanistic understanding of the immune signaling pathways activated. To exploit image-guided combination therapy, hypoxia signal from PET imaging was used to guide the addition of a hypoxia targeted treatment to nonresponsive tumors, which ultimately provided therapeutic synergy and rescued response as determined by longitudinal changes in tumor volume.ConclusionsThe results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.
| S-EPMC8776604 | biostudies-literature
Project description:Proliferation of aberrant, dysfunctional lymphatic vessels around solid tumors is a common histologic finding. Studies have shown that abnormalities in lymphatic function result in accumulation of inflammatory cells with an immunosuppressive profile. We tested the hypothesis that dysfunctional lymphatic vessels surrounding solid tumors regulate changes in the tumor microenvironment and tumor-specific immune responses. Using subcutaneously implanted mouse melanoma and breast cancer tumors in a lymphatic endothelial cell-specific diphtheria toxin receptor transgenic mouse, we found that local ablation of lymphatic vessels increased peritumoral edema, as compared with controls. Comparative analysis of the peritumoral fluid demonstrated increases in the number of macrophages, CD4+ inflammatory cells, F4/80+/Gr-1+ (myeloid-derived suppressor cells), CD4+/Foxp3+ (Tregs) immunosuppressive cells, and expression of inflammatory cytokines such as TNFα, IFNγ, and IL1β following lymphatic ablation. Tumors grown in lymphatic ablated mice exhibited reduced intratumoral accumulation of cytotoxic T cells and increased tumor PD-L1 expression, causing rapid tumor growth, compared with tumors grown in nonlymphatic-ablated mice. Our study suggests that lymphatic dysfunction plays a role in regulating tumor microenvironments and may be therapeutically targeted in combination with immunotherapy to prevent tumor growth and progression.
| S-EPMC6677612 | biostudies-literature
Project description:An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.
| S-EPMC10688992 | biostudies-literature
Project description:BACKGROUND. Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor β (TGF-β) inhibitor that targets cancer associated fibroblasts (CAFs) is promising to enhance efficacy of cancer immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy. METHODS. We measure CAFs in vivo using gallium 68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) for PET/CT imaging to guide TGF-β inhibition and sensitize metastatic colorectal cancer (CRC) to immunotherapy. A total of 131 patients with metastatic CRC underwent 68Ga-FAPI and 18F-fludeoxyglucose (18F-FDG) PET/CT imaging. Fourteen patients underwent surgery after the imaging. Relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed. Mouse cohorts of metastatic CRC were treated with TGF-β receptor (TGF-βR) inhibitor combined with KN046 which blocks PD-L1 and CTLA4, followed with 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses. RESULTS. Patients with metastatic CRC demonstrated high uptakes of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. TGF-βR inhibitor enhanced tumor infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamical changes of CAFs and tumor response to combined TGF-βR inhibitor with immunotherapy. CONCLUSION. 68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to stratify and guide patients with CRC for precise TGF-β inhibition plus immunotherapy, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.
2023-12-19 | GSE247303 | GEO
Project description:The therapeutic benefits of bilateral capsulotomy for the treatment of refractory obsessive compulsive disorder (OCD) are probably attributed to interruption of the cortico-striato-thalamo-cortical circuitry. We evaluated resting brain metabolism and treatment response in OCD patients using positron emission tomography (PET) imaging. [(18)F]-fluoro-deoxy-glucose PET was performed in eight OCD patients precapsulotomy and postcapsulotomy. We determined metabolic differences between preoperative images in patients and those in eight age-matched healthy volunteers, and postoperative changes and clinical correlations in the patients. The OCD patients showed widespread metabolic increases in normalized glucose metabolism in the bilateral orbitofrontal cortex and inferior frontal gyrus, cingulate gyrus, and bilateral pons/cerebellum, and metabolic decreases bilaterally in the precentral and lingual gyri. Bilateral capsulotomy resulted in significant metabolic decreases bilaterally in the prefrontal cortical regions, especially in the dorsal anterior cingulate cortex (ACC) and in the medial dorsal thalamus and caudate nucleus. In contrast, metabolism increased bilaterally in the precentral and lingual gyri. Clinical improvement in patients correlated with metabolic changes in the bilateral dorsal ACC and in the right middle occipital gyrus after capsulotomy. This study underscores the importance of the internal capsule in modulating ventral prefrontal and dorsal anterior cingulate neuronal activity in the neurosurgical management of OCD patients.
| S-EPMC3677106 | biostudies-literature
Project description:Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.
| S-EPMC7556869 | biostudies-literature
Project description:The microenvironment determines cell behavior, but the underlying molecular mechanisms are poorly understood because quantitative studies of cell signaling and behavior have been challenging due to insufficient spatial and/or temporal resolution and limitations on microenvironmental control. Here we introduce microenvironmental selective plane illumination microscopy (meSPIM) for imaging and quantification of intracellular signaling and submicrometer cellular structures as well as large-scale cell morphological and environmental features. We demonstrate the utility of this approach by showing that the mechanical properties of the microenvironment regulate the transition of melanoma cells from actin-driven protrusion to blebbing, and we present tools to quantify how cells manipulate individual collagen fibers. We leverage the nearly isotropic resolution of meSPIM to quantify the local concentration of actin and phosphatidylinositol 3-kinase signaling on the surfaces of cells deep within 3D collagen matrices and track the many small membrane protrusions that appear in these more physiologically relevant environments.
| S-EPMC4784259 | biostudies-literature
Project description:Gynecologic carcinosarcomas, previously known as malignant mixed Müllerian tumors, are uncommon malignancies that demonstrate an aggressive biology and lack a standard therapeutic approach. Molecular analyses have revealed recurrent alterations in chromatin remodeling genes, but clinical support for therapeutic significance is lacking. We prospectively identified a patient with refractory uterine carcinosarcoma whose tumor was subject to molecular profiling at diagnosis and again at radiographic progression. Initial molecular testing did not assess tumor mutational burden, DNA polymerase ɛ (POLE), or microsatellite status. After the failure of several lines of chemotherapy, comprehensive genomic profiling of a repeat biopsy identified two missense mutations of the exonuclease domain of POLE (P286R and T323A). Tumor mutational burden was elevated (169 mutations per DNA megabase), consistent with an ultramutator phenotype. As seen in previously reported POLE-endometrioid cases, our patient harbored alterations in PIK3CA, ARID1A, and PTEN and was microsatellite stable, with appreciable tumor-infiltrating lymphocytes. She achieved an ongoing durable response with pembrolizumab. This is the first report of programmed cell death protein 1 response in uterine carcinosarcoma. KEY POINTS:Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis.Inactivating DNA polymerase ɛ (POLE) mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition.To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma.This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB-high tumors.
| S-EPMC5947455 | biostudies-literature
Project description:Background & Aims: Hypoxia in the intestinal epithelium can be caused by acute ischemic events or conditions like Inflammatory Bowel Disease (IBD) where immune cell infiltration produces ‘inflammatory hypoxia’, a chronic condition that starves the mucosa of oxygen. Epithelial regeneration after ischemia and IBD suggests intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of acute and chronic hypoxia on human ISC (hISC) properties have not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs isolated from healthy human tissues. We then test the hypothesis that some inflammation-associated interleukins protect hISCs during prolonged hypoxia. Methods: hISCs were exposed to <1.0% oxygen in the MPS for 6-, 24-, 48- & 72hrs. Viability, HIF1a response, transcriptomics, cell cycle dynamics, and hISC response to cytokines were evaluated. Results: The novel MPS enables precise, real-time control and monitoring of oxygen levels at the cell surface. Under hypoxia, hISCs maintain viability until 72hrs and exhibit peak HIF1a at 24hrs. hISCs lose stem cell activity at 24hrs that recovers at 48hrs of hypoxia. Hypoxia increases the proportion of hISCs in G1 and regulates hISC capacity to respond to multiple inflammatory signals. Hypoxia induces hISCs to upregulate many interleukin receptors and hISCs demonstrate hypoxia-dependent cell cycle regulation and increased organoid forming efficiency when treated with specific interleukins Conclusions: Hypoxia primes hISCs to respond differently to interleukins than hISCs in normoxia through a transcriptional response. hISCs slow cell cycle progression and increase hISC activity when treated with hypoxia and specific interleukins. These findings have important implications for epithelial regeneration in the gut during inflammatory events.
2023-09-01 | GSE224973 | GEO