Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

Dampening inflammation by modulating tlr signalling

Cancer immunotherapy offers substantive benefit to patients with various tumour types, in some cases leading to complete tumour clearance. However, many patients do not respond to immunotherapy, galvanizing the field to define the mechanisms of pre-existing and acquired resistance. Interferon-γ (IFNγ) is a cytokine that has both protumour and antitumour activities, suggesting that it may serve as a nexus for responsiveness to immunotherapy. Many cancer immunotherapies and chemotherapies induce IFNγ production by various cell types, including activated T cells and natural killer cells. Patients resistant to these therapies commonly have molecular aberrations in the IFNγ signalling pathway or express resistance molecules driven by IFNγ. Given that all nucleated cells can respond to IFNγ, the functional consequences of IFNγ production need to be carefully dissected on a cell-by-cell basis. Here, we review the cells that produce IFNγ and the different effects of IFNγ in the tumour microenvironment, highlighting the pleiotropic nature of this multifunctional and abundant cytokine.

Interferon-γ: teammate or opponent in the tumour microenvironment?

Dendritic- cells (DCs) have received considerable attention as potential targets for the development of anticancer vaccines. DC-based anticancer vaccination relies on patient-derived DCs pulsed with a source of tumor-associated antigens (TAAs) in the context of standardized maturation-cocktails, followed by their reinfusion. Extensive evidence has confirmed that DC-based vaccines can generate TAA-specific, cytotoxic T cells. Nonetheless, clinical efficacy of DC-based vaccines remains suboptimal, reflecting the widespread immunosuppression within tumors. Thus, clinical interest is being refocused on DC-based vaccines as combinatorial partners for T cell-targeting immunotherapies. Here, we summarize the most recent preclinical/clinical development of anticancer DC vaccination and discuss future perspectives for DC-based vaccines in immuno-oncology.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2019.1638212

Trial Watch: Dendritic Cell Vaccination for Cancer Immunotherapy

Cancer cell growth is associated with immune surveillance failure. Nowadays, restoring the desired immune response against cancer cells remains a major therapeutic strategy. Due to the recent advances in biological knowledge, efficient therapeutic tools have been developed to support the best bio-clinical approaches for immune precision therapy. One of the most important successes in immune therapy is represented by the applicational use of monoclonal antibodies, particularly the use of rituximab for B-cell lymphoproliferative disorders. More recently, other monoclonal antibodies have been developed, to inhibit immune checkpoints within the tumor microenvironment that limit immune suppression, or to enhance some immune functions with immune adjuvants through different targets such as Toll-receptor agonists. The aim is to inhibit cancer proliferation by the diminishing/elimination of cancer residual cells and clinically improving the response duration with no or few adverse effects. This effect is supported by enhancing the number, functions, and activity of the immune effector cells, including the natural killer (NK) lymphocytes, NKT-lymphocytes, γδ T-lymphocytes, cytotoxic T-lymphocytes, directly or indirectly through vaccines particularly with neoantigens, and by lowering the functions of the immune suppressive cells. Beyond these new therapeutics and their personalized usage, new considerations have to be taken into account, such as epigenetic regulation particularly from microbiota, evaluation of transversal functions, particularly cellular metabolism, and consideration to the clinical consequences at the body level. The aim of this review is to discuss some practical aspects of immune therapy, giving to clinicians the concept of immune effector cells balancing between control and tolerance. Immunological precision medicine is a combination of modern biological knowledge and clinical therapeutic decisions in a global vision of the patient.

/pdf/immune-precision-medicine-for-cancer-a-novel-insight-based-12urjwoucv.pdf

Immune precision medicine for cancer: a novel insight based on the efficiency of immune effector cells

In the dark path of tumorigenesis, the more carefully the cancer biology is studied, the more brilliant answers could be given to the countless questions about its orchestrating derivers. The identification of the correlation between Toll-like receptors (TLRs) and different processes involved in carcinogenesis was one of the single points of blinding light highlighting the interconnection between the immune system and cancer. TLRs are a wide family of single-pass membrane-spanning receptors that have developed through the evolution to recognize the structurally conserved molecules derived from microorganisms or damaged cells. But this is not everything about these receptors as they could orchestrate several downstream signalling pathways leading to the formation or suppression of cancer cells. The present review is tempted to provide a concise schematic about the biology and the characters of TLRs and also summarize the major findings of the regulatory role of TLRs and their associated signalling in the pathogenesis of human cancers.

Toll-like receptors (TLRs): An old family of immune receptors with a new face in cancer pathogenesis

Immunotherapy using checkpoint blockade has revolutionized cancer treatment, improving patient survival and quality of life. Nevertheless, the clinical outcomes of such immunotherapy are highly heterogeneous between patients. Depending on the cancer type, the patient response rates to this immunotherapy are limited to 20-30%. Based on the mechanism underlying the antitumor immune response, new therapeutic strategies have been designed with the aim of increasing the effectiveness and specificity of the antitumor immune response elicited by checkpoint blockade agents. The activation of toll-like receptor 9 (TLR9) by its synthetic agonists induces the antitumor response within the innate immunity arm, generating adjuvant effects and priming the adaptive immune response elicited by checkpoint blockade during the effector phase of tumor-cell killing. This review first describes the underlying mechanisms of action and current status of monotherapy using TLR9 agonists and immune checkpoint inhibitors for cancer immunotherapy. The rationale for combining these two agents is discussed, and evidence indicating the current status of such combination therapy as a novel cancer treatment strategy is presented.

/pdf/adjuvant-effect-of-toll-like-receptor-9-activation-on-cancer-3phebivlds.pdf

Adjuvant Effect of Toll-Like Receptor 9 Activation on Cancer Immunotherapy Using Checkpoint Blockade.

Psoriasis, a complex inflammatory autoimmune skin disorder that affects 2-3% of the global population, is thought to be genetically predetermined and induced by environmental and immunological factors. In the past decades, basic and clinical studies have significantly expanded knowledge on the molecular, cellular, and immunological mechanisms underlying the pathogenesis of psoriasis. Based on these pathogenic mechanisms, the current disease model emphasizes the role of aberrant Th1 and Th17 responses. Th1 and Th17 immune responses are regulated by a complex network of different cytokines, including TNF-α, IL-17, and IL-23; signal transduction pathways downstream to the cytokine receptors; and various activated transcription factors, including NF-κB, interferon regulatory factors (IRFs), and signal transducer and activator of transcriptions (STATs). The biologics developed to specifically target the cytokines have achieved a better efficacy and safety for the systemic management of psoriasis compared with traditional treatments. Nevertheless, the current therapeutics can only alleviate the symptoms; there is still no cure for psoriasis. Therefore, the development of more effective, safe, and affordable therapeutics for psoriasis is important. In this review, we discussed the current trend of therapeutic development for psoriasis based on the recent discoveries in the immune modulation of the inflammatory response in psoriasis.

/pdf/therapeutic-development-based-on-the-immunopathogenic-e45mb43891.pdf

Therapeutic Development Based on the Immunopathogenic Mechanisms of Psoriasis.

https://www.mdpi.com/2076-393X/8/4/639/pdf

Chun Ming Huang

Papers

Adjuvant Effect of Toll-Like Receptor 9 Activation on Cancer Immunotherapy Using Checkpoint Blockade.

Therapeutic Development Based on the Immunopathogenic Mechanisms of Psoriasis.

Toll-Like Receptor 21 of Chicken and Duck Recognize a Broad Array of Immunostimulatory CpG-oligodeoxynucleotide Sequences.