Infiltration of macrophages in solid tumours is associated with poor prognosis and correlates with chemotherapy resistance in most cancers. In mouse models of cancer, macrophages promote cancer initiation and malignant progression by stimulating angiogenesis, increasing tumour cell migration, invasion and intravasation and suppressing antitumour immunity. At metastatic sites, macrophages promote tumour cell extravasation, survival and subsequent growth. Each of these pro-tumoural activities is promoted by a subpopulation of macrophages that express canonical markers but have unique transcriptional profiles, which makes tumour-associated macrophages (TAMs) good targets for anticancer therapy in humans through either their ablation or their re-differentiation away from pro-tumoural towards antitumoural states. In this Review, we evaluate the state of the art of TAM-targeting strategies, focusing on the limitations and potential side effects of the different therapies such as toxicity, rebound effects and compensatory mechanisms. We provide an extensive overview of the different types of therapy used in the clinic and their limitations in light of known macrophage biology and propose new strategies for targeting TAMs.

Targeting macrophages: therapeutic approaches in cancer.

The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies

/pdf/the-non-canonical-nf-kb-pathway-in-immunity-and-inflammation-3bcjq5jv0t.pdf

The non-canonical NF-κB pathway in immunity and inflammation.

The development of immunotherapies over the past decade has resulted in a paradigm shift in the treatment of cancer. However, the majority of patients do not benefit from immunotherapy, presumably owing to insufficient reprogramming of the immunosuppressive tumour microenvironment (TME) and thus limited reinvigoration of antitumour immunity. Various metabolic machineries and nutrient-sensing mechanisms orchestrate the behaviour of immune cells in response to nutrient availability in the TME. Notably, tumour-infiltrating immune cells typically experience metabolic stress as a result of the dysregulated metabolic activity of tumour cells, leading to impaired antitumour immune responses. Moreover, the immune checkpoints that are often exploited by tumour cells to evade immunosurveillance have emerging roles in modulating the metabolic and functional activity of T cells. Thus, repurposing of drugs targeting cancer metabolism might synergistically enhance immunotherapy via metabolic reprogramming of the TME. In addition, interventions targeting the metabolic circuits that impede antitumour immunity have been developed, with several clinical trials underway. Herein, we discuss how these metabolic circuits regulate antitumour immunity and the possible approaches to targeting these pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments that could be used to better unleash the potential of adoptive cell therapies by enhancing T cell metabolism.

/pdf/navigating-metabolic-pathways-to-enhance-antitumour-immunity-4b7zzfoskd.pdf

Navigating metabolic pathways to enhance antitumour immunity and immunotherapy

To dissect therapeutic mechanisms of transplanted stem cells and develop exosome-based nanotherapeutics in treating autoimmune and neurodegenerative diseases, we assessed the effect of exosomes secreted from human mesenchymal stem cells (MSCs) in treating multiple sclerosis using an experimental autoimmune encephalomyelitis (EAE) mouse model. We found that intravenous administration of exosomes produced by MSCs stimulated by IFNγ (IFNγ-Exo) (i) reduced the mean clinical score of EAE mice compared to PBS control, (ii) reduced demyelination, (iii) decreased neuroinflammation, and (iv) upregulated the number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) within the spinal cords of EAE mice. Co-culture of IFNγ-Exo with activated peripheral blood mononuclear cells (PBMCs) cells in vitro reduced PBMC proliferation and levels of pro-inflammatory Th1 and Th17 cytokines including IL-6, IL-12p70, IL-17AF, and IL-22 yet increased levels of immunosuppressive cytokine indoleamine 2,3-dioxygenase. IFNγ-Exo could also induce Tregs in vitro in a murine splenocyte culture, likely mediated by a third-party accessory cell type. Further, IFNγ-Exo characterization by deep RNA sequencing suggested that IFNγ-Exo contains anti-inflammatory RNAs, where their inactivation partially hindered the exosomes potential to induce Tregs. Furthermore, we found that IFNγ-Exo harbors multiple anti-inflammatory and neuroprotective proteins. These results not only shed light on stem cell therapeutic mechanisms but also provide evidence that MSC-derived exosomes can potentially serve as cell-free therapies in creating a tolerogenic immune response to treat autoimmune and central nervous system disorders.

/pdf/stem-cell-derived-exosomes-as-nanotherapeutics-for-3gnv4635mz.pdf

Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders.

The tumor microenvironment (TME) is a complex and ever-changing "rogue organ" composed of its own blood supply, lymphatic and nervous systems, stroma, immune cells and extracellular matrix (ECM). These complex components, utilizing both benign and malignant cells, nurture the harsh, immunosuppressive and nutrient-deficient environment necessary for tumor cell growth, proliferation and phenotypic flexibility and variation. An important aspect of the TME is cellular crosstalk and cell-to-ECM communication. This interaction induces the release of soluble factors responsible for immune evasion and ECM remodeling, which further contribute to therapy resistance. Other aspects are the presence of exosomes contributed by both malignant and benign cells, circulating deregulated microRNAs and TME-specific metabolic patterns which further potentiate the progression and/or resistance to therapy. In addition to biochemical signaling, specific TME characteristics such as the hypoxic environment, metabolic derangements, and abnormal mechanical forces have been implicated in the development of treatment resistance. In this review, we will provide an overview of tumor microenvironmental composition, structure, and features that influence immune suppression and contribute to treatment resistance.

/pdf/aspects-of-the-tumor-microenvironment-involved-in-immune-h3gg1ez4ek.pdf

Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance.

The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity.

A chimeric protein vaccine composed of the cholera toxin B subunit fused to proinsulin (CTB-INS) was shown to suppress type 1 diabetes onset in NOD mice and upregulate biosynthesis of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) in human dendritic cells (DCs). Here we demonstrate siRNA inhibition of the NF-κB-inducing kinase (NIK) suppresses vaccine-induced IDO1 biosynthesis as well as IKKα phosphorylation. Chromatin immunoprecipitation (ChIP) analysis of CTB-INS inoculated DCs showed that RelB bound to NF-κB consensus sequences in the IDO1 promoter, suggesting vaccine stimulation of the non-canonical NF-κB pathway activates IDO1 expression in vivo. The addition of Tumor Necrosis Factor Associated Factors (TRAF) TRAF 2, 3 and TRAF6 blocking peptides to vaccine inoculated DCs was shown to inhibit IDO1 biosynthesis. This experimental outcome suggests vaccine activation of the TNFR super-family receptor pathway leads to upregulation of IDO1 biosynthesis in CTB-INS inoculated dendritic cells. Together, our experimental data suggest the CTB-INS vaccine uses a TNFR-dependent signaling pathway of the non-canonical NF-κB signaling pathway resulting in suppression of dendritic cell mediated type 1 diabetes autoimmunity.

/pdf/chimeric-vaccine-stimulation-of-human-dendritic-cell-3xok4zddna.pdf

Chimeric Vaccine Stimulation of Human Dendritic Cell Indoleamine 2, 3-Dioxygenase Occurs via the Non-Canonical NF-κB Pathway

LPS enhances CTB-INSULIN induction of IDO1 and IL-10 synthesis in human dendritic cells.

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The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity.

Chimeric Vaccine Stimulation of Human Dendritic Cell Indoleamine 2, 3-Dioxygenase Occurs via the Non-Canonical NF-κB Pathway

LPS enhances CTB-INSULIN induction of IDO1 and IL-10 synthesis in human dendritic cells.