The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer

Science Immunology, Год журнала: 2022, Номер 7(75)

Опубликована: Сен. 9, 2022

The composition of the gut microbiome can control innate and adaptive immunity has emerged as a key regulator tumor growth, especially in context immune checkpoint blockade (ICB) therapy. However, underlying mechanisms for how affects growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory therapy, including ICB. Using nontargeted, liquid chromatography–tandem mass spectrometry–based metabolomic screen, we identified microbe–derived metabolite trimethylamine N -oxide (TMAO), which enhanced antitumor PDAC. Delivery TMAO intraperitoneally or via dietary choline supplement orthotopic PDAC-bearing mice reduced associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, activated effector T cell response microenvironment. Mechanistically, potentiated type I interferon (IFN) pathway conferred effects IFN–dependent manner. Delivering TMAO-primed macrophages intravenously produced similar effects. Combining ICB (anti-PD1 and/or anti-Tim3) mouse model PDAC significantly burden improved survival beyond alone. Last, levels bacteria containing CutC (an enzyme that generates trimethylamine, precursor) correlated long-term patients anti-PD1 melanoma. Together, our study identifies microbial driver lays groundwork potential therapeutic strategies targeting TMAO.

Язык: Английский

---

Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment

Gut, Год журнала: 2022, Номер 72(5), С. 958 - 971

Опубликована: Июнь 10, 2022

Innate immunity plays important roles in pancreatic ductal adenocarcinoma (PDAC), as non-T-cell-enriched tumour. Neutrophils are major players innate immune system. Here, we aimed to explore the heterogeneity and pro-tumour mechanisms of neutrophils PDAC.We analysed single-cell transcriptomes peripheral blood polymorphonuclear leucocytes (PMNs) tumour-infiltrating cells from five patients with PDAC, performed immunofluorescence/immunohistochemistry staining, multi-omics analysis vitro experiments validate discoveries bioinformatics analysis.Exploration tumour-associated (TANs) revealed a terminally differentiated subpopulation (TAN-1) associated poor prognosis, an inflammatory (TAN-2), population transitional stage that have just migrated tumour microenvironment (TAN-3) preferentially expressing interferon-stimulated genes (TAN-4). Glycolysis signature was upregulated along neutrophil transition trajectory, TAN-1 featured hyperactivated glycolytic activity. The switch TANs validated by integrative approach transcriptomics, proteomics metabolomics analysis. Activation activity LDHA overexpression induced immunosuppression functions neutrophil-like HL-60 (dHL-60) cells. Mechanistic studies BHLHE40, downstream hypoxia endoplasmic reticulum stress, key regulator polarisation towards phenotype, direct transcriptional regulation BHLHE40 on marker demonstrated chromatin immunoprecipitation assay. Pro-tumour were observed dHL-60 overexpressing BHLHE40. Importantly, immunohistochemistry PDAC tissues unfavourable prognostic value BHLHE40+ neutrophils.The dynamic properties this study will be helpful advancing therapy targeting immunity.

Язык: Английский

---

T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours

Nature Biomedical Engineering, Год журнала: 2021, Номер 5(11), С. 1246 - 1260

Опубликована: Июнь 3, 2021

Язык: Английский

---

LncRNA-PACERR induces pro-tumour macrophages via interacting with miR-671-3p and m6A-reader IGF2BP2 in pancreatic ductal adenocarcinoma

Journal of Hematology & Oncology, Год журнала: 2022, Номер 15(1)

Опубликована: Май 7, 2022

LncRNA-PACERR plays critical role in the polarization of tissue-associated macrophages (TAMs). In this study, we found function and molecular mechanism PACERR TAMs to regulate pancreatic ductal adenocarcinoma (PDAC) progression.We used qPCR analyse expression M1-tissue-resident (M1-NTRMs) which were isolated from 46 PDAC tissues. The on proliferation, migration invasion confirmed through vivo vitro assays. was discussed via fluorescence situ hybridization (FISH), RNA pull-down, ChIP-qPCR, RIP-qPCR luciferase assays.LncRNA-PACERR high associated with poor prognosis patients. Our finding validated that increased number M2-polarized cells facilized cell vivo. Mechanistically, activate KLF12/p-AKT/c-myc pathway by binding miR-671-3p. And bound IGF2BP2 acts as an m6A-dependent manner enhance stability KLF12 c-myc cytoplasm. addition, promoter a target recruited EP300 increase acetylation histone interacting nucleus.This study functions key regulator microenvironment revealed novel mechanisms cytoplasm nucleus.

Язык: Английский

---

Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Окт. 4, 2021

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years provides new opportunities to treat HCC. However, various etiologies can evade immune system through multiple mechanisms. With rapid development genetic engineering synthetic biology, variety novel immunotherapies have been employed advanced HCC, including checkpoint inhibitors, adoptive cell therapy, engineered cytokines, vaccines. In this review, we summarize current landscape research progress different strategies treatment The challenges field also discussed.

Язык: Английский

---

Pyroptosis Remodeling Tumor Microenvironment to Enhance Pancreatic Cancer Immunotherapy Driven by Membrane Anchoring Photosensitizer

Advanced Science, Год журнала: 2022, Номер 9(29)

Опубликована: Авг. 18, 2022

Abstract Immunotherapy, the most promising strategy of cancer treatment, has achieved outcomes, but its clinical efficacy in pancreatic is limited mainly due to complicated tumor immunosuppressive microenvironment. As a highly inflammatory form immunogenic cell death (ICD), pyroptosis provides great opportunity alleviate immunosuppression and promote systemic immune responses solid tumors. Herein, membrane‐targeted photosensitizer TBD‐3C with aggregation‐induced emission (AIE) feature trigger pyroptosis‐aroused immunotherapy via photodynamic therapy (PDT) applied. The results reveal that pyroptotic cells induced by could stimulate M1‐polarization macrophages, cause maturation dendritic (DCs), activation CD8 + cytotoxic T‐lymphocytes (CTLs). Pyroptosis‐aroused immunological convert “cold” microenvironment (TME) “hot” TME, which not only inhibits primary growth also attacks distant tumor. This work establishes platform high biocompatibility for light‐controlled antitumor immunity aroused pyroptosis.

Язык: Английский

---

Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies

Theranostics, Год журнала: 2022, Номер 12(3), С. 1030 - 1060

Опубликована: Янв. 1, 2022

Pancreatic tumors are highly desmoplastic and immunosuppressive. Delivery distribution of drugs within pancreatic compromised due to intrinsic physical biochemical stresses that lead increased interstitial fluid pressure, vascular compression, hypoxia. Immunotherapy-based approaches, including therapeutic vaccines, immune checkpoint inhibition, CAR-T cell therapy, adoptive T therapies, challenged by an immunosuppressive tumor microenvironment. Together, extensive fibrosis immunosuppression present major challenges developing treatments for cancer. In this context, nanoparticles have been extensively studied as delivery platforms adjuvants cancer other disease therapies. Recent advances in nanotechnology led the development multiple nanocarrier-based formulations not only improve drug but also enhance immunotherapy-based approaches This review discusses critically analyzes novel nanoscale strategies used immunomodulation treatment efficacy, newly emerging approaches. presents important perspectives on future research directions will guide rational design robust treat tumors, particularly with respect targeted therapies immunotherapies. These insights inform next generation clinical help patients manage debilitating survival rates.

Язык: Английский

---

Pan-Cancer Analysis Shows That ALKBH5 Is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Gliomas

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Апрель 4, 2022

Background AlkB homolog 5 (ALKBH5) is a N 6 -methyladenosine (m A) demethylase associated with the development, growth, and progression of multiple cancer types. However, biological role ALKBH5 has not been investigated in pan-cancer datasets. Therefore, this study, comprehensive bioinformatics analysis datasets was performed to determine mechanisms through which regulates tumorigenesis. Methods Online websites databases such as NCBI, UCSC, CCLE, HPA, TIMER2, GEPIA2, cBioPortal, UALCAN, STRING, SangerBox, ImmuCellAl, xCell, GenePattern were used extract data cancers. The patient analyzed relationship between expression, genetic alterations, methylation status, tumor immunity. Targetscan, miRWalk, miRDB, miRabel, LncBase Cytoscape tool identify microRNAs (miRNAs) long non-coding RNAs (lncRNAs) that regulate expression construct lncRNA-miRNA-ALKBH5 network. In vitro CCK-8, wound healing, Transwell M2 macrophage infiltration assays well vivo xenograft animal experiments functions glioma cells. Results showed upregulated several solid tumors. significantly correlated prognosis patients. Genetic alterations including duplications deep mutations gene identified Alterations prognosis. GO KEGG enrichment analyses ALKBH5-related genes enriched inflammatory, metabolic, immune signaling pathways glioma. checkpoint (ICP) genes, influenced sensitivity immunotherapy. We constructed lncRNA-miRNA network development progression. promoted proliferation, migration, invasion cells recruited Conclusions overexpressed types cancers regulation tumor-infiltration Our study shows promising prognostic immunotherapeutic biomarker some malignant

Язык: Английский

---

Artificial intelligence in pancreatic cancer

Theranostics, Год журнала: 2022, Номер 12(16), С. 6931 - 6954

Опубликована: Янв. 1, 2022

Pancreatic cancer is the deadliest disease, with a five-year overall survival rate of just 11%.The pancreatic patients diagnosed early screening have median nearly ten years, compared 1.5 years for those not screening.Therefore, diagnosis and treatment are particularly critical.However, as rare general cost high, accuracy existing tumor markers enough, efficacy methods exact.In terms diagnosis, artificial intelligence technology can quickly locate high-risk groups through medical images, pathological examination, biomarkers, other aspects, then lesions early.At same time, algorithm also be used to predict recurrence risk, metastasis, therapy response which could affect prognosis.In addition, widely in health records, estimating imaging parameters, developing computer-aided systems, etc. Advances AI applications will require concerted effort among clinicians, basic scientists, statisticians, engineers.Although it has some limitations, play an essential role overcoming foreseeable future due its mighty computing power.

Язык: Английский

---

Immunotherapy for hepatocellular carcinoma: Current status and future perspectives

World Journal of Gastroenterology, Год журнала: 2023, Номер 29(6), С. 1054 - 1075

Опубликована: Фев. 10, 2023

Hepatocellular carcinoma (HCC) is one of the world's deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in context chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation chemotherapy are common treatment options for HCC, however, they will only assist limited percentage patients. Current treatments advanced ineffective aggravate underlying condition. Despite promising preclinical early-phase clinical trials some drugs, existing systemic therapeutic methods tumor stages remain limited, underlining an unmet need. In current years, cancer immunotherapy has made significant progress, opening up new HCC. on other hand, variety causes can affects body's immune system via mechanisms. With speedy advancement synthetic biology genetic engineering, range innovative immunotherapies, such as checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, anti-PD ligand 1 death antibodies], vaccines, engineered cytokines, adoptive therapy have all been used this review, we summarize present landscape immunotherapies critically discuss recent trial outcomes, address future perspectives field cancer.

Язык: Английский

---