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Journal of Hepatology Sep 2023Recent literature has significantly advanced our knowledge and understanding of the tumour immune microenvironment of cholangiocarcinoma. Detailed characterisation of... (Review)
Review
Recent literature has significantly advanced our knowledge and understanding of the tumour immune microenvironment of cholangiocarcinoma. Detailed characterisation of the immune landscape has defined new patient subtypes. While not utilised in clinical practice yet, these novel classifications will help inform decisions regarding immunotherapeutic approaches. Suppressive immune cells, such as tumour-associated macrophages and myeloid-derived suppressor cells, form a barrier that shields tumour cells from immune surveillance. The presence of this immunosuppressive barrier in combination with a variety of immune escape mechanisms employed by tumour cells leads to poor tumour immunogenicity. Broad strategies to re-equip the immune system include blockade of suppressive immune cell recruitment to priming cytotoxic effector cells against tumour antigens. While immunotherapeutic strategies are gaining traction for the treatment of cholangiocarcinoma, there is a long road of discovery ahead in order to make meaningful contributions to patient therapy and survival.
Topics: Humans; Cholangiocarcinoma; Antigens, Neoplasm; Myeloid-Derived Suppressor Cells; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Tumor Microenvironment
PubMed: 37201670
DOI: 10.1016/j.jhep.2023.05.010 -
Cancer Research Jul 2023Tumor-associated macrophages (TAM), including antitumor M1-like TAMs and protumor M2-like TAMs, are transcriptionally dynamic innate immune cells with diverse roles in...
UNLABELLED
Tumor-associated macrophages (TAM), including antitumor M1-like TAMs and protumor M2-like TAMs, are transcriptionally dynamic innate immune cells with diverse roles in lung cancer development. Epigenetic regulators are key in controlling macrophage fate in the heterogeneous tumor microenvironment. Here, we demonstrate that the spatial proximity of HDAC2-overexpressing M2-like TAMs to tumor cells significantly correlates with poor overall survival of lung cancer patients. Suppression of HDAC2 in TAMs altered macrophage phenotype, migration, and signaling pathways related to interleukins, chemokines, cytokines, and T-cell activation. In coculture systems of TAMs and cancer cells, suppressing HDAC2 in TAMs resulted in reduced proliferation and migration, increased apoptosis of cancer cell lines and primary lung cancer cells, and attenuated endothelial cell tube formation. HDAC2 regulated the M2-like TAM phenotype via acetylation of histone H3 and transcription factor SP1. Myeloid cell-specific deletion of Hdac2 and pharmacologic inhibition of class I HDACs in four different murine lung cancer models induced the switch from M2-like to M1-like TAMs, altered infiltration of CD4+ and CD8+ T cells, and reduced tumor growth and angiogenesis. TAM-specific HDAC2 expression may provide a biomarker for lung cancer stratification and a target for developing improved therapeutic approaches.
SIGNIFICANCE
HDAC2 inhibition reverses the protumor phenotype of macrophages mediated by epigenetic modulation induced by the HDAC2-SP1 axis, indicating a therapeutic option to modify the immunosuppressive tumor microenvironment.
Topics: Animals; Mice; Macrophages; Lung Neoplasms; Cell Line; Myeloid Cells; Biomarkers; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37205635
DOI: 10.1158/0008-5472.CAN-22-1270 -
Cell Reports. Medicine Aug 2023Although radiotherapy (RT) has achieved great success in the treatment of non-small cell lung cancer (NSCLC), local relapses still occur and abscopal effects are rarely...
Although radiotherapy (RT) has achieved great success in the treatment of non-small cell lung cancer (NSCLC), local relapses still occur and abscopal effects are rarely seen even when it is combined with immune checkpoint blockers (ICBs). Here, we characterize the dynamic changes of tumor-infiltrating immune cells after RT in a therapy-resistant murine tumor model using single-cell transcriptomes and T cell receptor sequencing. At the early stage, the innate and adaptive immune systems are activated. At the late stage, however, the tumor immune microenvironment (TIME) shifts into immunosuppressive properties. Our study reveals that inhibition of CD39 combined with RT preferentially decreases the percentage of exhausted CD8 T cells. Moreover, we find that the combination of V-domain immunoglobulin suppressor of T cell activation (VISTA) blockade and RT synergistically reduces immunosuppressive myeloid cells. Clinically, high VISTA expression is associated with poor prognosis in patients with NSCLC. Altogether, our data provide deep insight into acquired resistance to RT from an immune perspective and present rational combination strategies.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neoplasm Recurrence, Local; Myeloid Cells; Tumor Microenvironment
PubMed: 37567173
DOI: 10.1016/j.xcrm.2023.101151 -
Science Translational Medicine Aug 2023Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively....
Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.
Topics: Animals; Mice; Antibodies, Monoclonal; Disease Models, Animal; Immunosuppressive Agents; Macrophages; Monocytes; Myeloid Cells; Triggering Receptor Expressed on Myeloid Cells-1
PubMed: 37647386
DOI: 10.1126/scitranslmed.add9990 -
Molecular Cell Jul 2023Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this...
Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2Fancd2 mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2Fancd2 HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.
Topics: Animals; Mice; Aging; Hematopoiesis; Tumor Suppressor Protein p53; DNA Damage; Aldehydes; Transcriptome; Single-Cell Gene Expression Analysis; Hematopoietic Stem Cells; Myeloid Cells; Humans; Leukemia, Myeloid, Acute
PubMed: 37348497
DOI: 10.1016/j.molcel.2023.05.035 -
Circulation Research Nov 2023Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly...
BACKGROUND
Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.
METHODS
Eight-week-old male and female C57BL/6J mice received either N-nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1β (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti-IL-1β antibody were utilized to deplete macrophages and IL-1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models.
RESULTS
N-nitro-L-arginine methyl ester/high-fat diet-treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68 cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1β in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in N-nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1β depletion also attenuated PH in N-nitro-L-arginine methyl ester/high-fat diet-treated mice.
CONCLUSIONS
We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell-derived IL-1β as an important contributor to PH in HFpEF.
Topics: Animals; Female; Humans; Male; Mice; Clodronic Acid; Heart Failure; Hypertension, Pulmonary; Interleukin-1beta; Mice, Inbred C57BL; Myeloid Cells; Stroke Volume
PubMed: 37929582
DOI: 10.1161/CIRCRESAHA.123.323119 -
Cell Metabolism Aug 2023Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic...
Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. To study IMH, we profiled tumor/normal regions from clear cell renal cell carcinoma (ccRCC) patients. A common pattern of IMH transcended all patients, characterized by correlated fluctuations in the abundance of metabolites and processes associated with ferroptosis. Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clinical significance of RNA biomarkers in ccRCC, we inferred metabolomic profiles from the RNA sequencing data of ccRCC patients enrolled in 7 clinical trials, and we ultimately identifyied metabolite biomarkers associated with response to anti-angiogenic agents. Local metabolic phenotypes, therefore, emerge in tandem with the immune microenvironment, influence ongoing tumor evolution, and are associated with therapeutic sensitivity.
Topics: Humans; Carcinoma, Renal Cell; Carcinoma; Myeloid Cells; RNA; Kidney Neoplasms; Tumor Microenvironment; Biomarkers, Tumor
PubMed: 37413991
DOI: 10.1016/j.cmet.2023.06.005 -
Nature Reviews. Clinical Oncology Feb 2024Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise... (Review)
Review
Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise of cancer treatments that modulate the immune system. However, the immune system is complex and dynamic, and can have both tumour-suppressive and tumour-promoting effects. Understanding the full range of immune modulation in cancer is crucial to identifying more effective treatment strategies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that develop in association with chronic inflammation, which is a hallmark of cancer. Indeed, MDSCs accumulate in the tumour microenvironment, where they strongly inhibit anticancer functions of T cells and natural killer cells and exert a variety of other tumour-promoting effects. Emerging evidence indicates that MDSCs also contribute to resistance to cancer treatments, particularly immunotherapies. Conversely, treatment approaches designed to eliminate cancer cells can have important additional effects on MDSC function, which can be either positive or negative. In this Review, we discuss the interplay between MDSCs and various other cell types found in tumours as well as the mechanisms by which MDSCs promote tumour progression. We also discuss the relevance and implications of MDSCs for cancer therapy.
Topics: Humans; Myeloid-Derived Suppressor Cells; Neoplasms; Myeloid Cells; Immunotherapy; T-Lymphocytes; Tumor Microenvironment
PubMed: 38191922
DOI: 10.1038/s41571-023-00846-y -
Hepatology (Baltimore, Md.) Jun 2024Microvascular invasion (MVI) is a crucial pathological hallmark of HCC that is closely associated with poor outcomes, early recurrence, and intrahepatic metastasis...
BACKGROUND AND AIMS
Microvascular invasion (MVI) is a crucial pathological hallmark of HCC that is closely associated with poor outcomes, early recurrence, and intrahepatic metastasis following surgical resection and transplantation. However, the intricate tumor microenvironment and transcriptional programs underlying MVI in HCC remain poorly understood.
APPROACH AND RESULTS
We performed single-cell RNA sequencing of 46,789 individual cells from 10 samples of MVI+ (MVI present) and MVI- (MVI absent) patients with HCC. We conducted comprehensive and comparative analyses to characterize cellular and molecular features associated with MVI and validated key findings using external bulk, single-cell, and spatial transcriptomic datasets coupled with multiplex immunofluorescence assays. The comparison identified specific subtypes of immune and stromal cells critical to the formation of the immunosuppressive and pro-metastatic microenvironment in MVI+ tumors, including cycling T cells, lysosomal associated membrane protein 3+ dendritic cells, triggering receptor expressed on myeloid cells 2+ macrophages, myofibroblasts, and arterial i endothelial cells. MVI+ malignant cells are characterized by high proliferation rates, whereas MVI- malignant cells exhibit an inflammatory milieu. Additionally, we identified the midkine-dominated interaction between triggering receptor expressed on myeloid cells 2+ macrophages and malignant cells as a contributor to MVI formation and tumor progression. Notably, we unveiled a spatially co-located multicellular community exerting a dominant role in shaping the immunosuppressive microenvironment of MVI and correlating with unfavorable prognosis.
CONCLUSIONS
This study provides a comprehensive single-cell atlas of MVI in HCC, shedding light on the complex multicellular ecosystem and molecular features associated with MVI. These findings deepen our understanding of the underlying mechanisms driving MVI and provide valuable insights for improving clinical diagnosis and developing more effective treatment strategies.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Tumor Microenvironment; Single-Cell Analysis; Neoplasm Invasiveness; Microvessels; Male; Female; Macrophages
PubMed: 37972953
DOI: 10.1097/HEP.0000000000000673 -
Nature Apr 2024Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct...
Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system.
Topics: Animals; Female; Humans; Male; Mice; Central Nervous System; Disease Models, Animal; Electron Transport; Electron Transport Complex I; Inflammation; Microglia; Mitochondria; Multiomics; Myeloid Cells; Neuroinflammatory Diseases; Reactive Oxygen Species
PubMed: 38480879
DOI: 10.1038/s41586-024-07167-9