Although considerable progress has been made in understanding how tumors evade immune surveillance, measures to counter the same have not kept pace with the advances made in designing effective ...strategies. 4-1BB (CD137; TNFRS9), an activation-induced costimulatory molecule, is an important regulator of immune responses. Targeting 4-1BB or its natural ligand 4-1BB ligand (4-1BBL) has important implications in many clinical conditions, including cancer. In depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes (CTL), and among others, high amounts of IFN-γ. In this review, we will discuss the various aspects of 4-1BB-mediated anti-tumor responses, the basis of such responses, and future directions.
Immunotherapy of cancer with 4-1BB Vinay, Dass S; Kwon, Byoung S
Molecular cancer therapeutics,
05/2012, Letnik:
11, Številka:
5
Journal Article
Recenzirano
4-1BB (CD137), a member of the TNF receptor superfamily, is an activation-induced T-cell costimulatory molecule. Signaling via 4-1BB upregulates survival genes, enhances cell division, induces ...cytokine production, and prevents activation-induced cell death in T cells. The importance of the 4-1BB pathway has been underscored in a number of diseases, including cancer. Growing evidence indicates that anti-4-1BB monoclonal antibodies possess strong antitumor properties, which in turn are the result of their powerful CD8+ T-cell activating, IFN-γ producing, and cytolytic marker-inducing capabilities. In addition, combination therapy of anti-4-1BB with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Furthermore, the adoptive transfer of ex vivo anti-4-1BB-activated CD8+ T cells from previously tumor-treated animals efficiently inhibits progression of tumors in recipient mice that have been inoculated with fresh tumors. In addition, targeting of tumors with variants of 4-1BBL directed against 4-1BB also have potent antitumor effects. Currently, a humanized anti-4-1BB is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, and ovarian cancer, and so far seems to have a favorable toxicity profile. In this review, we discuss the basis of the therapeutic potential of targeting the 4-1BB-4-1BBL pathway in cancer treatment.
Abstract Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade ...destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these ...studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC - high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV.
4-1BB (CD137) is an important T-cell stimulating molecule. The 4-1BB mAb or its variants have shown remarkable therapeutic activity against autoimmunity, viral infections, and cancer. Antibodies to ...4-1BB have recently entered clinical trials for the treatment of cancer with favorable toxicity profile. In this article, we present a review documenting the efficacy and pitfalls of 4-1BB therapy.
An extensive literature search has been made on 4-1BB, spanning two decades, and a comprehensive report is presented here highlighting the origins, biological effects, therapeutic potential, and mechanistic basis of targeting 4-1BB as well as the side effects associated with such therapy.
Research so far indicates that 4-1BB is highly protective against various pathological conditions including cancer. However, a few important side effects of 4-1BB therapy such as liver toxicity, thrombocytopenia, anemia, and suppressive effects on certain immune competent cells should be taken into consideration before it is used for human therapy.
4-1BB signaling beyond T cells Vinay, Dass S; Kwon, Byoung S
Cellular & molecular immunology,
07/2011, Letnik:
8, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Originally discovered as a T cell-activating molecule, 4-1BB (CD137) is now also recognized as an activator of non-T cells, thus imparting a new dimension to its potential in vivo effects. 4-1BB ...expression is seen on a variety of non-T cells including activated dendritic cells (DCs), monocytes, neutrophils, B cells and natural killer (NK) cells, and promotes their individual effector functions. The T cell- and non-T cell-activating ability of 4-1BB may be the basis of its powerful anti-cancer, anti-autoimmune and anti-viral effects. Here we discuss the consequence and importance of 4-1BB signaling in non-T cells. We consider its effects on immune regulation, and the distinct and/or overlapping pathways involved in these responses, as well as possible therapeutic applications.
Collagen type II-induced arthritis is a CD4(+) T-cell-dependent chronic inflammation in susceptible DBA/1 mice and represents an animal model of human rheumatoid arthritis. We found that development ...of this condition, and even established disease, are inhibited by an agonistic anti-4-1BB monoclonal antibody. Anti-4-1BB suppressed serum antibodies to collagen type II and CD4(+) T-cell recall responses to collagen type II. Crosslinking of 4-1BB evoked an antigen-specific, active suppression mechanism that differed from the results of blocking the interaction between 4-1BB and its ligand, 4-1BBL. Anti-4-1BB monoclonal antibodies induced massive, antigen-dependent clonal expansion of CD11c(+)CD8(+) T cells and accumulation of indoleamine 2,3-dioxygenase in CD11b(+) monocytes and CD11c(+) dendritic cells. Both anti-interferon-gamma and 1-methyltryptophan, a pharmacological inhibitor of indoleamine 2,3-dioxygenase, reversed the anti-4-1BB effect. We conclude that the suppression of collagen-induced arthritis was caused by an expansion of new CD11c(+)CD8(+) T cells, and that interferon-gamma produced by these cells suppresses antigen-specific CD4(+) T cells through an indoleamine 2,3-dioxygenase-dependent mechanism.
Rheumatoid arthritis (RA) is an inflammatory disease is one of the most serious medical problems, affecting ∼1% of all people worldwide, irrespective of race. The disease is autoimmune in nature and ...characterized by chronic inflammation of the synovial tissues in multiple joints that leads to joint destruction. Although T cells are central players in RA development, B cells are required for full penetrance of disease largely via their production of autoantibodies against Fc domain of IgG rheumatoid factor (RF). Treatment options for RA are limited and if any, are inadequate due to associated side effects. Members of the tumor necrosis factor (TNF) superfamily play important roles in a number of autoimmune diseases, including RA. In this review, we briefly summarize key features of the superfamily, we will consider how the well-characterized members concerned with immune regulation are coordinated and their roles in rheumatoid arthritis.
4-1BB (CD137) is an important T cell activating molecule. Here we report that it also promotes development of a distinct B cell subpopulation co-expressing PDCA-1. 4-1BB is expressed constitutively, ...and its expression is increased when PDCA-1(+) B cells are activated. We found that despite a high level of surface expression of 4-1BB on PDCA-1(+) B cells, treatment of these cells with agonistic anti-4-1BB mAb stimulated the expression of only a few activation markers (B7-2, MHC II, PD-L2), cytokines (IL-12p40/p70), and chemokines (MCP-1, RANTES), as well as sTNFR1, and the immunosuppressive enzyme, IDO. Although the PDCA-1(+) B cells stimulated by anti-4-1BB expressed MHC II at high levels and took up antigens efficiently, Ig class switching was inhibited when they were pulsed with T-independent (TI) or T-dependent (TD) Ags and adoptively transferred into syngeneic recipients. Furthermore, when anti-4-1BB-treated PDCA-1(+) B cells were pulsed with OVA peptide and combined with Vα2(+)CD4(+) T cells, Ag-specific cell division was inhibited both in vitro and in vivo. Our findings suggest that the 4-1BB signal transforms PDCA-1(+) B cells into propagators of negative immune regulation, and establish an important role for 4-1BB in PDCA-1(+) B cell development and function.
4‐1BB (CD137) is a costimulatory molecule involved in the activation and survival of CD4, CD8, and natural killer cells. Although a great deal has been learned as to how 4‐1BB‐mediated signaling ...governs the immunity of conventional T cells, the functional role of 4‐1BB in the context of CD4+CD25+ regulatory T cell (Tr) activation is largely unknown. Using 4‐1BB‐intact and ‐deficient mice, we investigated the effect of the 4‐1BB/4‐1BB ligand pathway on the suppressive function of Tr cells. Our data indicate that although 4‐1BB is expressed on Tr cells, its contribution to their proliferation is minimal. We also showed that signaling through the 4‐1BB receptor inhibited the suppressive function of Tr cells in vitro and in vivo. It is interesting that anti‐4‐1BB‐mediated but not anti‐GITR‐directed inhibition was more potent when Tr cells were preactivated. Collectively, these data indicate that 4‐1BB signaling is critical in Tr cell immunity.
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