Defining intrinsic and acquired mechanisms of immune checkpoint blockade resistance in glioblastoma
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PROVIDER: PRJNA1102116 | ENA |
REPOSITORIES: ENA
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Project description:Defining intrinsic and acquired mechanisms of immune checkpoint blockade resistance in glioblastoma
| PRJNA1102115 | ENA
Project description:Tumor-intrinsic signaling pathways can drastically affect the tumor immune microenvironment (TME), promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor-cell intrinsic pathways have been reported to modulate myeloid cell infiltration and subsequent T cell recruitment. Clinical evidence suggests that excluding cytotoxic T cells from the tumor core mediates resistance to immunotherapy. Here, we find that tumor cell-intrinsic SOX2 expression in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. CD8+ T cell exclusion was dependent on regulatory T cell-mediated suppression of tumor vasculature. Depleting tumor-infiltrating regulatory T cells via Glucocorticoid-Induced TNFR-Related protein (GITR) restored CD8+ T cell infiltration and, combined with checkpoint blockade therapy, reduced tumor growth.
2024-12-19 | GSE256071 | GEO
Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.
2023-11-08 | PXD039705 | Pride
Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.
2023-11-08 | PXD044987 | Pride
Project description:Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the IFN pathway that may be detrimental rather than beneficial. Effects of hMENA11a down-regulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes.
2023-08-30 | GSE224246 | GEO
Project description:Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the IFN pathway that may be detrimental rather than beneficial. Effects of hMENA11a down-regulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes.
2023-08-30 | GSE224216 | GEO
Project description:Despite the established use of immune checkpoint inhibitors to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and approximately 50% of patients whose tumors respond eventually develop acquired resistance. To identify novel drivers of acquired resistance, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed acquired resistance to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNɣ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia activated pro-drug delayed acquired resistance to immune checkpoint inhibitors in murine Msh2 KO tumors. Thus, this work provides rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.
2024-10-23 | GSE275877 | GEO
Project description:PROTACs (Proteolysis-Targeting Chimeras) represent a revolutionary new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to protein degraders remains poorly understood. Here, we applied proteomics approaches to elucidate resistance mechanisms to protein degrader therapies in cancer cells. Our studies revealed acquired resistance to degrader therapies in cancer cells can be mediated by upregulation of the ATP-dependent drug efflux pump MDR1. Degrader-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, MDR1 is frequently overexpressed in cancer, and cancer cell lines overexpressing MDR1 exhibited intrinsic resistance to protein degraders, requiring co-treatment with MDR1 inhibitors to achieve protein degradation and therapeutic response. Notably, co-treatment of MDR1-overexpressing K-ras mutant colorectal cancer cells with MEK1/2 or K-ras degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 activity and ErbB receptor-driven resistance. Together, our findings showed overexpression of MDR1 can promote both intrinsic and acquired resistance to protein degraders in cancer cells and that concurrent blockade of MDR1 will likely be required to achieve durable protein degradation and therapeutic response.
2022-10-06 | PXD029233 | Pride
Project description:The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being most over-represented1. While mitochondrial DNA (mtDNA) mutations have been associated with both improved and worsened prognoses in several tumour lineages, whether these mutations are drivers or exert any functional effect on tumour biology remains controversial. Here we discovered that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment promoting an anti-tumour immune response characterised by loss of resident neutrophils. This subsequently sensitised tumours bearing high mtDNA mutant heteroplasmy to immune checkpoint blockade, with phenocopy of key metabolic changes being sufficient to mediate this effect. Strikingly, patient lesions bearing >50% mtDNA mutation heteroplasmy also demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.
2023-03-13 | MSV000091475 | MassIVE
Project description:Coinhibitory receptor blockade is a promising strategy to boost immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for improved understanding of checkpoint blockade, but the T cell-intrinsic signaling pathways and gene expression profiles engaged during treatment are not well defined, particularly for combination approaches. We utilized a murine model of CD8+ T cell tolerance to address these issues. We used microarrays to examine the global transcriptional response of T cells rendered tolerant in vivo by encounter with tumor/self-antigen versus T cells activated in response to an immunogenic tumor. RNA isolated from naive Gag-specific T cells was compared to RNA isolated from T-cells transferred into B6 mice with established FBL tumor (immune) and from Alb:Gag mice (tolerant). Two days after T cell transfer, recipient spleen and lymph nodes were harvested and pooled. Transferred cells were then sorted based on CD8+ CD90.1+ CD69hi to a >96% purity using a FACSAria III (BD Biosciences). There were 3 biological replicates per condition.
2014-12-18 | E-GEOD-58722 | biostudies-arrayexpress