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Nature Communications Nov 2023Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may...
Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report a tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates for the targeted delivery of glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels the immunosuppressive TME to enhance ICI response. Poly β-amino ester (PAE)-modified PD-L1 and CTLA-4-antagonizing aptamers (aptPD-L1 and aptCTLA-4) are synthesized and co-assembled into supramolecular nanoassemblies for carrying BAY-876. The acidic tumor microenvironment causes PAE protonation and triggers nanoassembly dissociation to initiate BAY-876 and aptamer release. BAY-876 selectively inhibits TNBC glycolysis to deprive uridine diphosphate N-acetylglucosamine and downregulate PD-L1 N-linked glycosylation, thus facilitating PD-L1 recognition of aptPD-L1 to boost anti-PD-L1 therapy. Meanwhile, BAY-876 treatment also elevates glucose supply to tumor-residing regulatory T cells (Tregs) for metabolically rewiring them into an immunostimulatory state, thus cooperating with aptCTLA-4-mediated immune-checkpoint inhibition to abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms the immunosuppressive microenvironment in preclinical models of TNBC in female mice and provides a distinct approach for TNBC immunotherapy in the clinics.
Topics: Humans; Female; Animals; Mice; Triple Negative Breast Neoplasms; B7-H1 Antigen; Immune Checkpoint Inhibitors; Immunosuppression Therapy; DNA; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37919262
DOI: 10.1038/s41467-023-42883-2 -
Cell Research Jan 2024
Topics: Humans; Chromosomal Instability; Immunosuppression Therapy
PubMed: 37739994
DOI: 10.1038/s41422-023-00876-2 -
ACS Nano Jan 2024Mutation burden, hypoxia, and immunoediting contribute to altered metabolic profiles in tumor cells, resulting in a tumor microenvironment (TME) characterized by... (Review)
Review
Mutation burden, hypoxia, and immunoediting contribute to altered metabolic profiles in tumor cells, resulting in a tumor microenvironment (TME) characterized by accumulation of toxic metabolites and depletion of various nutrients, which significantly hinder the antitumor immunity multiple mechanisms, hindering the efficacy of tumor immunotherapies. In-depth investigation of the mechanisms underlying these phenomena are vital for developing effective antitumor drugs and therapies, while the therapeutic effects of metabolism-targeting drugs are restricted by off-target toxicity toward effector immune cells and high dosage-mediated side effects. Nanotechnologies, which exhibit versatility and plasticity in targeted delivery and metabolism modulation, have been widely applied to boost tumor immunometabolic therapies multiple strategies, including targeting of metabolic pathways. In this review, recent advances in understanding the roles of tumor cell metabolism in both immunoevasion and immunosuppression are reviewed, and nanotechnology-based metabolic reprogramming strategies for enhanced tumor immunotherapies are discussed.
Topics: Humans; Immunotherapy; Immunosuppression Therapy; Neoplasms; Antineoplastic Agents; Nanotechnology; Tumor Microenvironment
PubMed: 38180952
DOI: 10.1021/acsnano.3c11260 -
The Journal of Clinical Investigation Sep 2023Suppression of antitumor immunity is a prominent feature of the tumor microenvironment. In this issue of the JCI, Taves, Otsuka, and authors show that glucocorticoids...
Suppression of antitumor immunity is a prominent feature of the tumor microenvironment. In this issue of the JCI, Taves, Otsuka, and authors show that glucocorticoids (GCs), which are potent immunosuppressive hormones mainly produced by the adrenals, can be reconverted from their inactive form to active metabolites via the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme expressed by murine tumor cell lines. In the tumor microenvironment, GCs acted on CD4+ regulatory T cells to enhance their immunosuppressive function and promote tumor growth. The findings suggest that targeting GC recycling as a strategy for modulating tumor immunosuppression has the potential to improve therapeutic efficacy of immune checkpoint blockade.
Topics: Animals; Mice; Glucocorticoids; T-Lymphocytes, Regulatory; Immunosuppression Therapy; Immunosuppressive Agents; 11-beta-Hydroxysteroid Dehydrogenase Type 1
PubMed: 37712416
DOI: 10.1172/JCI173141 -
Practical Neurology Aug 2023Autoimmune neuromuscular diseases are common and often treatable causes for peripheral nervous system dysfunction. If not optimally managed, they result in meaningful...
Autoimmune neuromuscular diseases are common and often treatable causes for peripheral nervous system dysfunction. If not optimally managed, they result in meaningful impairments and disability. The treating neurologist should aim to maximise clinical recovery with minimal iatrogenic risk. This requires careful patient and medication selection, appropriate counselling and close monitoring of clinical efficacy and safety. Here, we summarise our consensus departmental approach to first-line immunosuppression in neuromuscular diseases. We combine multispecialty evidence and expertise with a focus on autoimmune neuromuscular diseases to create guidance on starting, dosing and monitoring for toxic effects of the commonly used drugs. These include corticosteroids, steroid-sparing agents and cyclophosphamide. We also provide efficacy monitoring advice, as clinical response informs dosage and drug choice. The principles of this approach could be applied across much of the spectrum of immune-mediated neurological disorders where there is significant therapeutic crossover.
Topics: Humans; Neuromuscular Diseases; Immunosuppression Therapy
PubMed: 37173131
DOI: 10.1136/pn-2023-003708 -
Liver Transplantation : Official... Jun 2024This review discusses long-term complications from immunosuppressants after liver transplantation and the management of these complications. Common complications of... (Review)
Review
This review discusses long-term complications from immunosuppressants after liver transplantation and the management of these complications. Common complications of calcineurin inhibitors include nephrotoxicity and metabolic diseases. Nephrotoxicity can be managed by targeting a lower drug level and/or adding an immunosuppressant of a different class. Metabolic disorders can be managed by treating the underlying condition and targeting a lower drug level. Gastrointestinal adverse effects and myelosuppression are common complications of antimetabolites that are initially managed with dose reduction or discontinuation if adverse events persist. Mammalian targets of rapamycin inhibitors are associated with myelosuppression, proteinuria, impaired wound healing, and stomatitis, which may require dose reduction or discontinuation. Induction agents and agents used for steroid-refractory rejection or antibody-mediated rejection are reviewed. Other rare complications of immunosuppressants are discussed as well.
Topics: Humans; Immunosuppressive Agents; Liver Transplantation; Graft Rejection; Calcineurin Inhibitors; Kidney Diseases; Immunosuppression Therapy; Metabolic Diseases; MTOR Inhibitors
PubMed: 38315054
DOI: 10.1097/LVT.0000000000000341 -
Journal For Immunotherapy of Cancer Nov 2023G-protein-coupled receptor 84 (GPR84) marks a subset of myeloid-derived suppressor cells (MDSCs) with stronger immunosuppression in the tumor microenvironment. Yet, how...
BACKGROUNDS
G-protein-coupled receptor 84 (GPR84) marks a subset of myeloid-derived suppressor cells (MDSCs) with stronger immunosuppression in the tumor microenvironment. Yet, how GPR84 endowed the stronger inhibition of MDSCs to CD8 T cells function is not well established. In this study, we aimed to identify the underlying mechanism behind the immunosuppression of CD8 T cells by GPR84 MDSCs.
METHODS
The role and underlying mechanism that MDSCs or exosomes (Exo) regulates the function of CD8 T cells were investigated using immunofluorescence, fluorescence activating cell sorter (FACS), quantitative real-time PCR, western blot, ELISA, Confocal, RNA-sequencing (RNA-seq), etc. In vivo efficacy and mechanistic studies were conducted with wild type, GPR84 and p53 knockout C57/BL6 mice.
RESULTS
Here, we showed that the transfer of GPR84 from MDSCs to CD8 T cells via the Exo attenuated the antitumor response. This inhibitory effect was also observed in GPR84-overexpressed CD8 T cells, whereas depleting GPR84 elevated CD8 T cells proliferation and function in vitro and in vivo. RNA-seq analysis of CD8 T cells demonstrated the activation of the p53 signaling pathway in CD8 T cells treated with GPR84 MDSCs culture medium. While knockout p53 did not induce senescence in CD8 T cells treated with GPR84 MDSCs. The per cent of GPR84 CD8 T cells work as a negative indicator for patients' prognosis and response to chemotherapy.
CONCLUSIONS
These data demonstrated that the transfer of GPR84 from MDSCs to CD8 T cells induces T-cell senescence via the p53 signaling pathway, which could explain the strong immunosuppression of GPR84 endowed to MDSCs.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Immunosuppression Therapy; Myeloid-Derived Suppressor Cells; Receptors, G-Protein-Coupled; T-Cell Exhaustion; Tumor Suppressor Protein p53
PubMed: 38016719
DOI: 10.1136/jitc-2023-007802 -
Developmental Cell Dec 2023How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated...
How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated in dedifferentiated tumor cells, limits the number of infiltrating T lymphocytes in premalignant lesions of mouse basal-like breast cancer. SOX9-mediated immunosuppression is required for the progression of in situ tumors to invasive carcinoma. SOX9 induces the expression of immune checkpoint B7x/B7-H4 through STAT3 activation and direct transcriptional regulation. B7x is upregulated in dedifferentiated tumor cells and protects them from immunosurveillance. B7x also protects mammary gland regeneration in immunocompetent mice. In advanced tumors, B7x targeting inhibits tumor growth and overcomes resistance to anti-PD-L1 immunotherapy. In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8 T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer.
Topics: Animals; Female; Humans; Mice; Breast Neoplasms; CD8-Positive T-Lymphocytes; Immunosuppression Therapy; SOX9 Transcription Factor; V-Set Domain-Containing T-Cell Activation Inhibitor 1
PubMed: 37963469
DOI: 10.1016/j.devcel.2023.10.010 -
Molecular Medicine (Cambridge, Mass.) Jul 2023The main cause of high mortality from sepsis is that immunosuppression leads to life-threatening organ dysfunction, and reversing immunosuppression is key to sepsis...
BACKGROUND
The main cause of high mortality from sepsis is that immunosuppression leads to life-threatening organ dysfunction, and reversing immunosuppression is key to sepsis treatment. Interferon γ (IFNγ) is a potential therapy for immunosuppression of sepsis, promoting glycolysis to restore metabolic defects in monocytes, but the mechanism of treatment is unclear.
METHODS
To explore the immunotherapeutic mechanism of IFNγ, this study linked the Warburg effect (aerobic glycolysis) to immunotherapy for sepsis and used cecal ligation perforation (CLP) and lipopolysaccharide (LPS) to stimulate dendritic cells (DC) to establish in vivo and in vitro sepsis models, Warburg effect inhibitors (2-DG) and PI3K pathway inhibitors (LY294002) were used to explore the mechanism by which IFNγ regulates immunosuppression in mice with sepsis through the Warburg effect.
RESULTS
IFNγ markedly inhibited the reduction in cytokine secretion from lipopolysaccharide (LPS)-stimulated splenocytes. IFNγ-treated mice had significantly increased the percentages of positive costimulatory receptor CD86 on Dendritic cells expressing and expression of splenic HLA-DR. IFNγ markedly reduced DC-cell apoptosis by upregulating the expression of Bcl-2 and downregulating the expression of Bax. CLP-induced formation of regulatory T cells in the spleen was abolished in IFNγ -treated mice. IFNγ treatment reduced the expression of autophagosomes in DC cells. IFNγ significant reduce the expression of Warburg effector-related proteins PDH, LDH, Glut1, and Glut4, and promote glucose consumption, lactic acid, and intracellular ATP production. After the use of 2-DG to suppress the Warburg effect, the therapeutic effect of IFNγ was suppressed, demonstrating that IFNγ reverses immunosuppression by promoting the Warburg effect. Moreover, IFNγ increased the expression of phosphoinositide 3-kinases (PI3K), protein kinase B (Akt), rapamycin target protein (mTOR), hypoxia-inducible factor-1 (HIF-1α), pyruvate dehydrogenase kinase (PDK1) protein, the use of 2-DG and LY294002 can inhibit the expression of the above proteins, LY294002 also inhibits the therapeutic effect of IFNγ.
CONCLUSIONS
It was finally proved that IFNγ promoted the Warburg effect through the PI3K/Akt/mTOR pathway to reverse the immunosuppression caused by sepsis. This study elucidates the potential mechanism of the immunotherapeutic effect of IFNγ in sepsis, providing a new target for the treatment of sepsis.
Topics: Animals; Mice; Immunosuppression Therapy; Interferon-gamma; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sepsis
PubMed: 37434129
DOI: 10.1186/s10020-023-00690-x -
Immunological Investigations Nov 2023Colorectal cancer (CRC) is the third most prevalent malignancy with increased incidence and mortality rates worldwide. Traditional treatment approaches have attempted to... (Review)
Review
Colorectal cancer (CRC) is the third most prevalent malignancy with increased incidence and mortality rates worldwide. Traditional treatment approaches have attempted to efficiently target CRC; however, they have failed in most cases, owing to the cytotoxicity and non-specificity of these therapies. Therefore, it is essential to develop an effective alternative therapy to improve the clinical outcomes in heterogeneous CRC cases. Immunotherapy has transformed cancer treatment with remarkable efficacy and overcomes the limitations of traditional treatments. With an understanding of the cancer-immunity cycle and tumor microenvironment evolution, current immunotherapy approaches have elicited enhanced antitumor immune responses. In this comprehensive review, we outline the latest advances in immunotherapy targeting CRC and provide insights into antitumor immune responses reported in landmark clinical studies. We focused on highlighting the combination approaches that synergistically induce immune responses and eliminate immunosuppression. This review aimed to understand the limitations and potential of recent immunotherapy clinical studies conducted in the last five years (2019-2023) and to transform this knowledge into a rational design of clinical trials intended for effective antitumor immune responses in CRC.
Topics: Humans; Colorectal Neoplasms; Immunotherapy; Immunosuppression Therapy; Tumor Microenvironment
PubMed: 37812224
DOI: 10.1080/08820139.2023.2264906