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Epigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancer

ABSTRACT: T cell exhaustion (TEX) represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally-exhausted state. Here, we employed an epigenetic drug screen and identified BET inhibitors (BETis) as enhancers of effector functions in primary exhausted T cells from malignant pleural effusions in lung cancer patients. Transcriptomics, metabolomics, and ATAC-seq analyses revealed that BETis reinvigorate TEX by activating the polyamine biosynthesis pathway, expanding intracellular polyamine pools, and altering chromatin accessibility. Genetic and pharmacological inhibition of ornithine decarboxylase (ODC1), a key enzyme in this pathway, abolished BETi-mediated immunopotentiation. Single-cell RNA-seq demonstrated BETis reduced terminal TEX while promoting progenitor TEX through activation of the MYC-ODC axis. BETi treatment or adoptive transfer of BETi-treated T cells suppressed malignant pleural effusion formation in a syngeneic lung cancer model. These findings highlight an epigenetic-metabolic approach to enhance TEX plasticity and offers insights for novel cancer immunotherapies.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Miao-Hsia Lin

PROVIDER: PXD060100 | JPOST Repository | Mon Apr 06 00:00:00 BST 2026

REPOSITORIES: jPOST

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			Action	DRS
	20221003_324_JQ1_pos_DDA_5ul_1.raw	Raw
	20221003_324_JQ1_pos_DDA_5ul_2.raw	Raw
	20221003_324_JQ1_pos_MS1_5ul_1.raw	Raw
	20221003_324_JQ1_pos_MS1_5ul_2.raw	Raw
	20221003_324_JQ1_pos_MS1_5ul_3.raw	Raw

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Epigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancer [RNA-seq]

Project description:T cell exhaustion (TEX) represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally-exhausted state. Here, we employed an epigenetic drug screen and identified BET inhibitors (BETis) as enhancers of effector functions in primary exhausted T cells from malignant pleural effusions in lung cancer patients. Transcriptomics, metabolomics, and ATAC-seq analyses revealed that BETis reinvigorate TEX by activating the polyamine biosynthesis pathway, expanding intracellular polyamine pools, and altering chromatin accessibility. Genetic and pharmacological inhibition of ornithine decarboxylase (ODC), a key enzyme in this pathway, abolished BETi-mediated immunopotentiation. Single-cell RNA-seq demonstrated BETis reduced terminal TEX while promoting progenitor TEX through activation of the MYC-ODC axis. BETi treatment or adoptive transfer of BETi-treated T cells suppressed malignant pleural effusion formation in a syngeneic lung cancer model. These findings highlight an epigenetic-metabolic approach to enhance TEX plasticity and offers insights for novel cancer immunotherapies.

2026-04-05 | GSE287799 | GEO

Epigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancer [ATAC-seq]

2026-04-05 | GSE287798 | GEO

Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

Project description:Background: Lung cancer is the leading cause of cancer related death worldwide. Over the past 15 years no major improvement of survival rates could be accomplished. The recently discovered histone methyltransferase KMT9 as epigenetic regulator of prostate tumor growth has now raised hopes of enabling new cancer therapies. In this study we aimed to identify the function of KMT9 in lung cancer which has remained elusive so far. Methods: We linked full transcriptome and proteome analyses of A549 lung adenocarcinoma cells using RNA-Seq and mass spectrometry with functional cell culture, real-time proliferation and flow cytometry assays. Results: KMT9 is expressed in lung cancer tissue and cell lineswith high levels of KMT9 correlating with poor patient survival. We identified 460 overlapping genes and proteins that are deregulated upon knock-down of KMT9alpha in A549 cells. These genes cluster with proliferation, cell cycle and cell death gene sets as well as with subcellular organelles in gene ontology analysis. Knock-down of KMT9alpha inhibits lung cancer cell proliferation and induces non-apoptotic cell death in A549 cells. Conclusions: The novel histone methyltransferase KMT9 is crucial for proliferation and survival of lung cancer cells harboring various mutations. Small molecule inhibitors targeting KMT9 therefore should be further examined as potential milestones in modern epigenetic lung cancer therapy.

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Large-scale epigenetic reprogramming is punctuated late during the evolution of pancreatic cancer progression [ChIP-Seq]

Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. Chip-Seq (K27Me3, K36Me3, K9Me2/3, K4Me3 and K27Ac) of 2 patients (A13 and A38) and HPDE cell line. Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets), and 6AN treated and DMSO samples for lung matastasis. Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates.

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Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

Project description:The IRE1α-XBP1 arm of the unfolded protein response (UPR) has emerged as a central orchestrator of malignant progression and immunosuppression in various cancer types. Yet the role of this pathway in non-small cell lung cancer (NSCLC) has remained largely unexplored. Using an RNA-seq based computational XBP1s detection method applied to TCGA datasets, we uncovered that expression of the IRE1a-generated XBP1s mRNA isoform predicts poor survival in NSCLC patients. Ablation of IRE1a in malignant cells delayed tumor progression and extended survival in an XBP1-dependent fashion in mouse models of NSCLC. This protective effect was accompanied by marked alterations in both lymphoid and myeloid intratumoral cell subsets that elicited durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustained mPGES-1 expression, enabling production of the immunosuppressive lipid mediator PGE2 in the tumor microenvironment (TME). Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescued normal tumor progression. By identifying the dominant transcriptional networks controlled by IRE1α in mouse lung tumors, we further developed a new gene signature that predicted immune cell infiltration and overall survival in human NSCLC. Hence, our study unveils a key immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.

2022-05-13 | GSE202939 | GEO

Large-scale epigenetic reprogramming is punctuated late during the evolution of pancreatic cancer progression [BS-Seq]

Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. BS-Seq of 4 patients (A13, A38, A124 and A125). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets). Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates. Patient A124 included 2 primary tumors and 1 normal pancreas.

2016-10-24 | E-GEOD-63123 | biostudies-arrayexpress

Large-scale epigenetic reprogramming is punctuated late during the evolution of pancreatic cancer progression [RNA-Seq]

Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. RNA-Seq of 2 patients (A13 and A38). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets), and 6AN treated and DMSO control samples. Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates.

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The immunopeptidome landscape associated with T cell infiltration, inflammation and immune-editing in lung cancer

Project description:One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. While patients with CD3+CD8+ T cell inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown if the repertoire of HLA bound peptides presented in highly inflamed and non-inflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent non-malignant lung tissues from eight lung cancer patients and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics and explored the heterogeneous expression and presentation of tumor (neo)antigens. Here we associated diverse immune cell populations with the immunopeptidome in CD3+CD8+ T cell excluded, infiltrated, highly- and lowly-inflamed tumors. We found evidence for lower immune-editing and higher presentation efficiency of tumor-associated antigens in lowly-inflamed and CD3+CD8+ T cell excluded tumors. This could have implications for the choice of combination therapies tailored to the patient’s mutanome and microenvironment.

2023-03-21 | PXD034772 | Pride

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