Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy ...represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4
T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.
Astragalus polysaccharides (APS), which is widely used as a remedy to promote immunity of breast cancer patients, can enhance immune responses and exert anti-tumor effects. In this study, we ...investigated the effects and mechanisms of APS on macrophage RAW 264.7 and EAC tumor-bearing mice. Griess reaction and ELISA assays revealed that the concentrations of nitric oxide, TNF-α, IL-1β and IL-6 were increased by APS. However, this effect was diminished in the presence of TAK-242 (TLR4 inhibitor) or ST-2825(MyD88 inhibitor). In C57BL/10J (TLR4
wild-type) and C57BL/6J (MyD88
wild-type) tumor-bearing mice, the tumor apoptosis rate, immune organ indexes and the levels of TNF-α, IL-1β and IL-6 in blood increased and the tumor weight decreased by oral administration of APS for 25 days. APS had no obvious effects on IL-12p70. However, these effects were not significant in C57BL/10ScNJ (TLR4-deficient) and C57BL/B6.129P2(SJL)-Myd88
/J (MyD88-deficient) tumor-bearing mice. qRT-PCR and Western blot indicated that APS stimulated the key nodes in the TLR4-MyD88 dependent signaling pathway, including TLR4, MyD88, TRAF-6, NF-κB and AP-1, both in vitro and in vivo. However, TRAM was an exception. Moreover, TRAF-6 and NF-κB were not triggered by APS in gene-deficient tumor-bearing mice. Therefore, APS may modulate immunity of host organism through activation of TLR4-mediated MyD88-dependent signaling pathway.
The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 ...cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.
Innate immunity represents the semi-specific first line of defense and provides the initial host response to tissue injury, trauma, and pathogens. Innate immunity activates the adaptive immunity, and ...both act highly regulated together to establish and maintain tissue homeostasis. Any dysregulation of this interaction can result in chronic inflammation and autoimmunity and is thought to be a major underlying cause in the initiation and progression of highly prevalent immune-mediated inflammatory diseases (IMIDs) such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases among others, and periodontitis. Th1 and Th2 cells of the adaptive immune system are the major players in the pathogenesis of IMIDs. In addition, Th17 cells, their key cytokine IL-17, and IL-23 seem to play pivotal roles. This review aims to provide an overview of the current knowledge about the differentiation of Th17 cells and the role of the IL-17/IL-23 axis in the pathogenesis of IMIDs. Moreover, it aims to review the association of these IMIDs with periodontitis and briefly discusses the therapeutic potential of agents that modulate the IL-17/IL-23 axis.
Mucosa-associated invariant T (MAIT) cells are a large innate-like T-cell subset in humans defined by invariant TCR Vα7.2 use and expression of CD161. MAIT cells recognize microbial riboflavin ...metabolites of bacterial or fungal origin presented by the monomorphic MR1 molecule. The extraordinary level of evolutionary conservation of MR1 and the limited known diversity of riboflavin metabolite antigens have suggested that MAIT cells are relatively homogeneous and uniform in responses against diverse microbes carrying the riboflavin biosynthesis pathway. The ability of MAIT cells to exhibit microbe-specific functional specialization has not been thoroughly investigated. Here, we found that MAIT cell responses against Escherichia coli and Candida albicans displayed microbe-specific polyfunctional response profiles, antigen sensitivity, and response magnitudes. MAIT cell effector responses against E. coli and C. albicans displayed differential MR1 dependency and TCR β-chain bias, consistent with possible divergent antigen subspecificities between these bacterial and fungal organisms. Finally, although the MAIT cell immunoproteome was overall relatively homogenous and consistent with an effector memory-like profile, it still revealed diversity in a set of natural killer cell-associated receptors. Among these, CD56, CD84, and CD94 defined a subset with higher expression of the transcription factors promyelocytic leukemia zinc finger (PLZF), eomesodermin, and T-bet and enhanced capacity to respond to IL-12 and IL-18 stimulation. Thus, the conserved and innate-like MAIT cells harbor multiple layers of functional heterogeneity as they respond to bacterial or fungal organisms or innate cytokines and adapt their antimicrobial response patterns in a stimulus-specific manner.
Management of Crohn Disease: A Review Cushing, Kelly; Higgins, Peter D R
JAMA : the journal of the American Medical Association,
2021-Jan-05, Letnik:
325, Številka:
1
Journal Article
Recenzirano
Crohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term complications, ...including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance.
The optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti-tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4β7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy.
The treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.
Many solid cancers contain dysfunctional immune microenvironments. Immune system modulators that initiate responses to foreign pathogens could be promising candidates for reigniting productive ...responses toward tumors. Interleukin-1 (IL-1) and IL-12 cytokine family members cooperate at barrier tissues after microbial invasion, in human inflammatory diseases, and in antitumoral immunity. IL-36γ, in classic alarmin fashion, acts in damaged tissues, whereas IL-23 centrally coordinates immune responses to danger signals. In this study, direct intratumoral delivery of messenger RNAs (mRNAs) encoding these cytokines produced robust anticancer responses in a broad range of tumor microenvironments. The addition of mRNA encoding the T cell costimulator OX40L increased complete response rates in treated and untreated distal tumors compared to the cytokine mRNAs alone. Mice exhibiting complete responses were subsequently protected from tumor rechallenge. Treatments with these mRNA mixtures induced downstream cytokine and chemokine expression, and also activated multiple dendritic cell (DC) and T cell types. Consistent with this, efficacy was dependent on Batf3-dependent cross-presenting DCs and cytotoxic CD8
T cells. IL-23/IL-36γ/OX40L triplet mRNA mixture triggered substantial immune cell recruitment into tumors, enabling effective tumor destruction irrespective of previous tumoral immune infiltrates. Last, combining triplet mRNA with checkpoint blockade led to efficacy in models otherwise resistant to systemic immune checkpoint inhibition. Human cell studies showed similar cytokine responses to the individual components of this mRNA mixture, suggesting translatability of immunomodulatory activity to human patients.
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