Publications by authors named "Dario A A Vignali"

Article Synopsis
  • Cancer treatment is shifting towards immunotherapy, with immune checkpoint inhibitors (ICIs) showing promising results in improving patient survival rates.
  • The FDA has recently approved a combination therapy involving LAG3 and PD1 inhibitors for advanced melanoma patients, paving the way for further research.
  • Ongoing clinical trials are exploring new LAG3-targeted treatments, including bispecific antibodies that aim to reactivate exhausted T cells in the fight against cancer.
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Article Synopsis
  • Understanding the relationship between breast cancer and its microenvironment is crucial for improving treatment and outcomes.
  • Researchers identified two distinct transcriptomic subtypes and five immune infiltration patterns in a study of 21 estrogen receptor-positive (ER+) and HER2-negative invasive lobular carcinomas (ILCs).
  • A notable finding was that a proliferative subtype had higher levels of suppressive immune cells, while a specific gene signature linked to lower proliferation and more pro-inflammatory tumor-associated macrophages indicated better survival rates in ER+ breast cancer patients.
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Expression of T cell Ig and mucin domain-containing protein 3 (Tim-3) is upregulated on regulatory T cells (Tregs) during chronic viral infections. In several murine and human chronic infections, the expression of Tim-3 is associated with poor control of viral burden and impaired antiviral immune responses. However, the role of Tim-3+ Tregs during persistent viral infections has not been fully defined.

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EBV-induced gene 3 (Ebi3) is a β subunit within the IL-12 cytokine family that canonically binds to α subunits p19, p28, or p35 to form the heterodimeric cytokines IL-39, IL-27, and IL-35, respectively. In the last decade, the binding partners for Ebi3 have continued to expand to include IL-6 and the other IL-12 family β subunit p40, revealing the possibility that Ebi3 may be able to bind to other cytokines and have distinct functions. We first explored this possibility utilizing an in vivo mouse model of regulatory T cell-restricted deletions of the subunits composing the cytokine IL-35, p35, and Ebi3, and we observed a differential impact on CD8+ T cell inhibitory receptor expression despite comparable reduction in tumor growth.

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Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8 T cell receptor signaling and altered CD8 T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile.

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Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown.

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Article Synopsis
  • Exhausted CD8 T cells in chronic viral infections and cancer express inhibitory receptors (IRs) like PD-1, which can be blocked to reinvigorate T cell function.
  • Co-targeting multiple IRs, such as PD-1 and LAG-3, can enhance T cell response and disease control beyond blocking PD-1 alone.
  • The study reveals distinct functions of PD-1 and LAG-3 in T cell activity, showing LAG-3's role in T cell durability and in creating a subset of T cells that are more effective at killing cancer or infected cells.
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Article Synopsis
  • Researchers are exploring ways to reverse or limit the lack of regulatory T cells (Tregs) to improve immunotherapy for autoimmune diseases like type 1 diabetes.
  • In a study of NOD mice, Tregs found in the pancreas (intraislet Tregs) showed a dysfunctional phenotype, lacking a key receptor called neuropilin-1 (Nrp1), which is essential for Treg stability and function.
  • Restoring Nrp1 expression in Tregs demonstrated a protective effect against the onset of autoimmune diabetes, suggesting that maintaining Nrp1 signaling could be a potential strategy for addressing Treg deficiencies in autoimmune diseases.
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Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF).

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Lymphocyte activation gene 3 (LAG3) is an inhibitory receptor that plays a critical role in controlling T cell tolerance and autoimmunity and is a major immunotherapeutic target. LAG3 is expressed on the cell surface as a homodimer but the functional relevance of this is unknown. In this study, we show that the association between the TCR/CD3 complex and a murine LAG3 mutant that cannot dimerize is perturbed in CD8+ T cells.

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CD4 T cells recognize peptide antigens presented on class II major histocompatibility complex (MHC-II) molecules to carry out their function. The remarkable diversity of T cell receptor sequences and lack of antigen discovery approaches for MHC-II make profiling the specificities of CD4 T cells challenging. We have expanded our platform of signaling and antigen-presenting bifunctional receptors to encode MHC-II molecules presenting covalently linked peptides (SABR-IIs) for CD4 T cell antigen discovery.

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Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes.

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The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau.

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Article Synopsis
  • * T cell exhaustion is a process where T cells become less effective due to continuous stimulation from antigens, leading to limited growth, high expression of inhibitory receptors, and reduced ability to combat infections or cancer.
  • * The text reviews the characteristics and causes of T cell exhaustion, focusing on the transcriptional and epigenetic changes involved, and discusses potential strategies for enhancing T cell function, particularly in cancer treatment.
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Human regulatory T cells (T) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of T for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted T is important, yet the transcriptional programs that control intratumoral T gene expression, and that are distinct from T in healthy tissues, remain largely unknown.

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Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that is highly expressed by exhausted T cells. LAG-3 is a promising immunotherapeutic target, with more than 20 LAG-3-targeting therapeutics in clinical trials and a fixed-dose combination of anti-LAG-3 and anti-PD-1 now approved to treat unresectable or metastatic melanoma. Although LAG-3 is widely recognized as a potent inhibitory receptor, important questions regarding its biology and mechanism of action remain.

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Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology.

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The spread of prion-like protein aggregates is believed to be a common driver of pathogenesis in many neurodegenerative diseases. Accumulated tangles of filamentous Tau protein are considered pathogenic lesions of Alzheimer's disease (AD) and related Tauopathies, including progressive supranuclear palsy, and corticobasal degeneration. Tau pathologies in these illnesses exhibits a clear progressive and hierarchical spreading pattern that correlates with disease severity.

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The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI.

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Article Synopsis
  • - Regulatory T (T) cells play a crucial role in maintaining immune balance by preventing excessive inflammation and tissue damage through various mechanisms, including the release of anti-inflammatory cytokines and metabolic disruption.
  • - Exposure to interferon gamma (IFNγ) during viral infections leads to T cells adopting an effector-like state while remaining functional, which is influenced by the presence of the IFNγ receptor but not the interleukin 12 receptor.
  • - T1-like T cells limit the effectiveness of CD8 T cell responses during infections, highlighting how the immune system adapts to inflammatory signals to control immune responses and the formation of memory T cells.
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T cell-centric immunotherapies have shown modest clinical benefit thus far for estrogen receptor-positive (ER) breast cancer. Despite accounting for 70% of all breast cancers, relatively little is known about the immunobiology of ER breast cancer in women with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). To investigate this, we performed phenotypic, transcriptional and functional analyses for a cohort of treatment-naive IDC (n = 94) and ILC (n = 87) tumors.

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Unlabelled: Breast cancer, the most common type of cancer affecting women, encompasses a collection of histologic (mainly ductal and lobular) and molecular subtypes exhibiting diverse clinical presentation, disease trajectories, treatment options, and outcomes. Immunotherapy has revolutionized treatment for some solid tumors but has shown limited promise for breast cancers. In this review, we summarize recent advances in our understanding of the complex interactions between tumor and immune cells in subtypes of breast cancer at the cellular and microenvironmental levels.

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