Regulatory T cells in the tumour microenvironment.

The powerful suppressive capabilities of regulatory T (T) cells and their appreciable contribution to tumour progression make them attractive immunotherapeutic targets. However, their role in systemic immune homeostasis makes it important to find ways to specifically target tumour-infiltrating T cells while leaving the wider system unperturbed. It is also unknown whether therapies depleting or disrupting the function of tumour-infiltrating T cells will provide the greatest efficacy while limiting immune-related adverse events.

Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs.

Lymphocyte activation gene 3 (LAG3) has emerged as a promising cancer immunotherapy target, but the mechanism underlying LAG3 activation upon ligand engagement remains elusive. Here, LAG3 was found to undergo robust non-K48-linked polyubiquitination upon ligand engagement, which promotes LAG3's inhibitory function instead of causing degradation. This ubiquitination could be triggered by the engagement of major histocompatibility complex class II (MHC class II) and membrane-bound (but not soluble) fibrinogen-like protein 1 (FGL1).

Regulatory T cells in the tumor microenvironment display a unique chromatin accessibility profile.

Regulatory T cells (Tregs) are a suppressive CD4+ T cell population that limit the antitumor immune response. In this study, we analyzed the chromatin accessibility of Tregs in the murine tumor microenvironment (TME) to identify tumor-specific accessible peaks and if these are altered over time in the tumor microenvironment, with or without anti-PD-1 immunotherapy. We found that despite little change in chromatin accessibility of Tregs in the tumor over time, Tregs have a distinct chromatin accessibility signature in the TME compared with Tregs in the periphery.

Neuronal LAG3 facilitates pathogenic α-synuclein neuron-to-neuron propagation.

Lymphocyte activation gene 3 (LAG3) is a key receptor involved in the propagation of pathological proteins in Parkinson's disease (PD). This study investigates the role of neuronal LAG3 in mediating the binding, uptake, and propagation of α-synuclein (αSyn) preformed fibrils (PFFs). Using neuronal LAG3 conditional knockout mice and human induced pluripotent stem cells-derived dopaminergic (DA) neurons, we demonstrate that LAG3 expression is critical for pathogenic αSyn propagation.

Ebi3 Binding to IFN-γ and IL-10 Limits Their Function.

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.

Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8 T cells to promote antitumor immunity.

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.

LAG-3 and PD-1 synergize on CD8 T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity.

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.

Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.

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).

Cutting Edge: LAG3 Dimerization Is Required for TCR/CD3 Interaction and Inhibition of Antitumor Immunity.

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.

Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission.

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.

Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells.

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.

LAG-3 as the third checkpoint inhibitor.

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.

Pathological Tau transmission initiated by binding lymphocyte-activation gene 3.

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.

Epitope Mapping of Therapeutic Antibodies Targeting Human LAG3.

Lymphocyte activation gene 3 protein (LAG3; CD223) is an inhibitory receptor that is highly upregulated on exhausted T cells in tumors and chronic viral infection. Consequently, LAG3 is now a major immunotherapeutic target for the treatment of cancer, and many mAbs against human (h) LAG3 (hLAG3) have been generated to block its inhibitory activity. However, little or no information is available on the epitopes they recognize.

Therapeutic targeting of regulatory T cells in cancer.

The success of immunotherapy in oncology underscores the vital role of the immune system in cancer development. Regulatory T cells (Tregs) maintain a fine balance between autoimmunity and immune suppression. They have multiple roles in the tumor microenvironment (TME) but act particularly in suppressing T cell activation.

Antibodies targeting conserved non-canonical antigens and endemic coronaviruses associate with favorable outcomes in severe COVID-19.

While there have been extensive analyses characterizing cellular and humoral responses across the severity spectrum in COVID-19, outcome predictors within severe COVID-19 remain less comprehensively elucidated. Furthermore, properties of antibodies (Abs) directed against viral antigens beyond spike and their associations with disease outcomes remain poorly defined. We perform deep molecular profiling of Abs directed against a wide range of antigenic specificities in severe COVID-19 patients.

Autoreactive CD8 T cells are restrained by an exhaustion-like program that is maintained by LAG3.

Impaired chronic viral and tumor clearance has been attributed to CD8 T cell exhaustion, a differentiation state in which T cells have reduced and altered effector function that can be partially reversed upon blockade of inhibitory receptors. The role of the exhaustion program and transcriptional networks that control CD8 T cell function and fate in autoimmunity is not clear. Here we show that intra-islet CD8 T cells phenotypically, transcriptionally, epigenetically and metabolically possess features of canonically exhausted T cells, yet maintain important differences.

Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells.

Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.