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Journal of the American Academy of... Mar 2017Psoriasis is a common chronic inflammatory disease of the skin that is increasingly being recognized as a systemic inflammatory disorder. Psoriatic arthritis is a... (Review)
Review
Psoriasis is a common chronic inflammatory disease of the skin that is increasingly being recognized as a systemic inflammatory disorder. Psoriatic arthritis is a well-known comorbidity of psoriasis. A rapidly expanding body of literature in various populations and settings supports additional associations between psoriasis and cardiometabolic diseases, gastrointestinal diseases, kidney disease, malignancy, infection, and mood disorders. The pathogenesis of comorbid disease in patients with psoriasis remains unknown; however, shared inflammatory pathways, cellular mediators, genetic susceptibility, and common risk factors are hypothesized to be contributing elements. As additional psoriasis comorbidities continue to emerge, education of health care providers is essential to ensuring comprehensive medical care for patients with psoriasis.
Topics: Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Dyslipidemias; Humans; Infections; Inflammatory Bowel Diseases; Liver Diseases; Mood Disorders; Neoplasms; Obesity; Prevalence; Psoriasis; Renal Insufficiency, Chronic
PubMed: 28212759
DOI: 10.1016/j.jaad.2016.07.064 -
Nature Biomedical Engineering Aug 2018Tumour-associated macrophages are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance...
Tumour-associated macrophages are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet, macrophages are highly plastic and can also acquire an anti-tumorigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNP-R848) lead to efficient drug delivery to tumour-associated macrophages in vivo. As a monotherapy, the administration of CDNP-R848 in multiple tumour models in mice altered the functional orientation of the tumour immune microenvironment towards an M1 phenotype, leading to controlled tumour growth and protecting the animals against tumour rechallenge. When used in combination with the immune checkpoint inhibitor anti-PD-1, we observed improved immunotherapy response rates, including in a tumour model resistant to anti-PD-1 therapy alone. Our findings demonstrate the ability of rationally engineered drug-nanoparticle combinations to efficiently modulate tumour-associated macrophages for cancer immunotherapy.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Imidazoles; Immunotherapy; Macrophages; Mice; Nanoparticles; Neoplasms; Toll-Like Receptor 7; Toll-Like Receptor 8; Tumor Microenvironment
PubMed: 31015631
DOI: 10.1038/s41551-018-0236-8 -
Journal of the American Academy of... Mar 2017As summarized in the first article in this continuing medical education series, the currently available epidemiologic data suggest that psoriasis may be a risk factor... (Review)
Review
As summarized in the first article in this continuing medical education series, the currently available epidemiologic data suggest that psoriasis may be a risk factor for cardiometabolic disease. Emerging data also suggest associations between psoriasis and other comorbidities beyond psoriatic arthritis, including chronic kidney disease, inflammatory bowel disease, hepatic disease, certain malignancies, infections, and mood disorders. Recognizing the comorbid disease burden of psoriasis is essential for ensuring comprehensive care of patients with psoriasis. The clinical implications of the comorbid diseases that are associated with psoriasis and recommendations for clinical management are reviewed in this article.
Topics: Cardiovascular Diseases; Comorbidity; Contraindications; Diabetes Mellitus; Dyslipidemias; Humans; Immunosuppressive Agents; Infections; Inflammatory Bowel Diseases; Liver Diseases; Mood Disorders; Obesity; Psoriasis; Renal Insufficiency, Chronic; Risk Factors; Skin Neoplasms; Tumor Necrosis Factor-alpha
PubMed: 28212760
DOI: 10.1016/j.jaad.2016.07.065 -
Journal For Immunotherapy of Cancer Sep 2021Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of...
BACKGROUND
Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments.
METHODS
TLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein-protein interaction analysis.
RESULTS
Results demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro. In vivo, the intratumoral synergistic combination of poly(I:C)+R848 significantly prevented tumor growth and metastasis in lung cancer and fibrosarcoma immunocompetent murine models. Regressing tumors showed increased infiltration of macrophages with a higher M1:M2 ratio, recruitment of CD4 and CD8 T cells, accompanied by a reduction of immunosuppressive CD206 TAMs and FOXP3/CD4 T cells. The depletion of both CD4 and CD8 T cells resulted in complete loss of treatment efficacy. Treated mice acquired systemic antitumoral response and resistance to tumor rechallenge mediated by boosted macrophage cytotoxic activity and T-cell proliferation. Proteomic experiments validate the superior activation of innate immunity by poly(I:C)+R848 combination versus single treatments or poly(I:C)+R837, and protein-protein-interaction network analysis reveal the key activation of the STAT1 pathway.
DISCUSSION
These findings demonstrate the antitumor immune responses mediated by macrophage activation on local administration of poly(I:C)+R848 combination and support the intratumoral application of this therapy to patients with solid tumors in the clinic.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Combined Modality Therapy; Drug Synergism; Humans; Imidazoles; Immunotherapy; Mice; Neoplasms; Poly I-C; Tumor-Associated Macrophages
PubMed: 34531246
DOI: 10.1136/jitc-2021-002408 -
Nature Communications Mar 2021Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune...
Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. Herein, we investigate whether localized delivery of the TLR agonist, resiquimod (R848), via platelet membrane-coated nanoparticles (PNP-R848) elicits antitumor responses. The membrane coating provides a means of enhancing interactions with the tumor microenvironment, thereby maximizing the activity of R848. Intratumoral administration of PNP-R848 strongly enhances local immune activation and leads to complete tumor regression in a colorectal tumor model, while providing protection against repeated tumor re-challenges. Moreover, treatment of an aggressive breast cancer model with intratumoral PNP-R848 delays tumor growth and inhibits lung metastasis. Our findings highlight the promise of locally delivering immunostimulatory payloads using biomimetic nanocarriers, which possess advantages such as enhanced biocompatibility and natural targeting affinities.
Topics: Animals; Blood Platelets; Breast Neoplasms; Cell Line, Tumor; Cell Membrane; Cells, Cultured; Female; HT29 Cells; Humans; Imidazoles; Immunotherapy; Lung Neoplasms; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Treatment Outcome; Tumor Microenvironment; Mice
PubMed: 33790276
DOI: 10.1038/s41467-021-22311-z -
Nature Communications Sep 2023The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC),...
The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8 T cells, especially stem-like CD8 T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPs) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPs target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPs-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8 T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8 T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8 T cell proliferation and differentiation to terminally exhausted CD8 T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.
Topics: Male; Animals; Mice; Tumor-Associated Macrophages; alpha-Fetoproteins; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Liver Neoplasms; Immunosuppressive Agents; Antigens, Neoplasm; Tumor Microenvironment
PubMed: 37704614
DOI: 10.1038/s41467-023-41438-9 -
Journal For Immunotherapy of Cancer Jul 2022Stereotactic body radiotherapy (SBRT) has been increasingly used as adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC), and induces immunogenic cell death,...
BACKGROUND
Stereotactic body radiotherapy (SBRT) has been increasingly used as adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC), and induces immunogenic cell death, which leads to the release of tumor antigen and damage-associated molecular patterns. However, this induction often fails to generate sufficient response to overcome pre-existing tumor microenvironment (TME) immunosuppression. Toll-like receptor (TLR) 7/8 ligands, such as R848, can amplify the effect of tumor vaccines, with recent evidence showing its antitumor effect in pancreatic cancer by modulating the immunosuppressive TME. Therefore, we hypothesized that the combination of R848 and SBRT would improve local and systemic antitumor immune responses by potentiating the antitumor effects of SBRT and reversing the immunosuppressive nature of the PDAC TME.
METHODS
Using murine models of orthotopic PDAC, we assessed the combination of intravenous TLR7/8 agonist R848 and local SBRT on tumor growth and immune response in primary pancreatic tumors. Additionally, we employed a hepatic metastatic model to investigate if the combination of SBRT targeting only the primary pancreatic tumor and systemic R848 is effective in controlling established liver metastases.
RESULTS
We demonstrated that intravenous administration of the TLR7/8 agonist R848, in combination with local SBRT, leads to superior tumor control compared with either treatment alone. The combination of R848 and SBRT results in significant immune activation of the pancreatic TME, including increased tumor antigen-specific CD8 T cells, decreased regulatory T cells, and enhanced antigen-presenting cells maturation, as well as increased interferon gamma, granzyme B, and CCL5 along with decreased levels of interleukin 4 (IL-4), IL-6, and IL-10. Importantly, the combination of SBRT and systemic R848 also resulted in similar immunostimulatory changes in liver metastases, leading to improved metastatic control. CD8 T cell depletion studies highlighted the necessity of these effector cells at both the local and hepatic metastatic sites. T cell receptor (TCR) clonotype analysis indicated that systemic R848 not only diversified the TCR repertoire but also conditioned the metastatic foci to facilitate entry of CD8 T cells generated by SBRT therapy.
CONCLUSIONS
These findings suggest that systemic administration of TLR7/8 agonists in combination with SBRT may be a promising avenue for metastatic PDAC treatment.
Topics: Adjuvants, Immunologic; Animals; Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Humans; Imidazoles; Liver Neoplasms; Mice; Pancreatic Neoplasms; Radiosurgery; Toll-Like Receptor 7; Toll-Like Receptor 8; Tumor Microenvironment
PubMed: 35851308
DOI: 10.1136/jitc-2022-004784 -
Oncoimmunology Jul 2020Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally... (Review)
Review
Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and Drug Administration for the topical treatment of actinic keratosis and genital warts more than 20 years ago. Both resiquimod and motolimod operate as agonists of Toll-like receptor 7 (TLR7) and/or TLR8, in thus far delivering adjuvant-like signals to antigen-presenting cells (APCs). In line with such an activity, these compounds are currently investigated as immunostimulatory agents for the treatment of various malignancies, especially in combination with peptide-based, dendritic cell-based, cancer cell lysate-based, or DNA-based vaccines. Here, we summarize preclinical and clinical evidence recently collected to support the development of resiquimod and motolimod and other TLR7/TLR8 agonists as anticancer agents.
Topics: Adjuvants, Immunologic; Antineoplastic Agents; Imiquimod; Toll-Like Receptor 7; Toll-Like Receptor 8; United States
PubMed: 32934889
DOI: 10.1080/2162402X.2020.1796002 -
Journal of Controlled Release :... Jan 2021The development of successful vaccines has been increasingly reliant on the use of immunoadjuvants - additives, which can enhance and modulate immune responses to... (Review)
Review
The development of successful vaccines has been increasingly reliant on the use of immunoadjuvants - additives, which can enhance and modulate immune responses to vaccine antigens. Immunoadjuvants of the polyphosphazene family encompass synthetic biodegradable macromolecules, which attain in vivo activity via antigen delivery and immunostimulation mechanisms. Over the last decades, the technology has witnessed evolvement of next generation members, expansion to include various antigens and routes of administration, and progression to clinical phase. This was accompanied by gaining important insights into the mechanism of action and the development of a novel class of virus-mimicking nano-assemblies for antigen delivery. The present review evaluates in vitro and in vivo data generated to date in the context of latest advances in understanding the primary function and biophysical behavior of these macromolecules. It also provides an overview of relevant synthetic and characterization methods, macromolecular biodegradation pathways, and polyphosphazene-based multi-component, nanoparticulate, and microfabricated formulations.
Topics: Adjuvants, Immunologic; Organophosphorus Compounds; Polymers; Vaccines
PubMed: 33285104
DOI: 10.1016/j.jconrel.2020.12.001 -
Frontiers in Pharmacology 2017Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only... (Review)
Review
Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc.
PubMed: 28620298
DOI: 10.3389/fphar.2017.00304