Role of Th1 and Th2 cytokines in BCG-induced IFN-gamma production: cytokine promotion and simulation of BCG effect.
ABSTRACT Induction of a T-helper-type 1 (Th1) immune response is indispensable for successful treatment of superficial bladder cancer with BCG. In this study possible involvement of various cytokines in BCG action as well as their potential roles in enhancing and mimicking BCG effect were explored. In immunocompetent cell cultures, IFN-gamma, a major Th1 cytokine, appears to be a late responsive cytokine to BCG stimulation. Its induction requires involvement of various endogenously produced Th1 and Th2 cytokines. Functional abolishment of any one of these cytokines (IL-2, IL-6, IL-12, IL-18, GMCSF, TNF-alpha, or IFN-alpha, except IL-10) by neutralizing antibodies leads to reduced IFN-gamma production (19-82% inhibition in mouse and 44-77% inhibition in human systems, respectively). In mice cytokines IL-2, IL-12, IL-18, and GMCSF are observed to synergize with BCG for IFN-gamma production, whereas in human cytokines IL-2, IL-12, TNF-alpha, and IFN-alpha exhibit similar synergistic effects. Rational combinations of these Th1-stimulating cytokines (IL-12 plus IL-18 in mice and IL-2 plus IL-12 in humans, respectively) dramatically up-regulate IFN-gamma production that is incomparably superior to BCG for induction of this cytokine. These results suggest that combined Th1-stimulating cytokines and combinations of BCG plus selected Th1-stimulating cytokines are rational candidates for further study in the treatment of bladder cancer patients.
- SourceAvailable from: Mathieu F Chevalier[Show abstract] [Hide abstract]
ABSTRACT: Bladder cancer is a common urologic malignancy with rising incidence in the elderly population. In most cases, bladder cancer is non-muscle invasive at diagnosis. Although current treatments often strongly reduce the risk of disease progression, bladder cancer shows dramatically high recurrence rates. Immunotherapy using intravesical instillation of Bacillus Calmette-Guérin (BCG) remains the most effective therapy for patients with high risk tumors. However, BCG-therapy has important limitations including substantial adverse events and frequent treatment failure. Thus, it appears crucial to either improve or replace current therapy using new immunotherapeutic strategies. Here, we discuss the clinical trials that assessed therapeutic vaccination of bladder cancer patients using tumor associated antigens and we also argue for novel approaches arising from murine models. Vaccination routes to induce appropriate T-cell homing in the tumor site as well as the use of local immunostimulation to enhance recruitment of vaccine-induced T cells are discussed to highlight what we believe is a promising therapeutic vaccination strategy for patients with non-muscle invasive bladder cancer.Human Vaccines and Therapeutics 01/2014; 10(4). · 3.64 Impact Factor
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ABSTRACT: Bacillus Calmette-Guérin (BCG) has been used to treat non-muscle-invasive bladder cancer for more than 30 years. It is one of the most successful biotherapies for cancer in use. Despite long clinical experience with BCG, the mechanism of its therapeutic effect is still under investigation. Available evidence suggests that urothelial cells (including bladder cancer cells themselves) and cells of the immune system both have crucial roles in the therapeutic antitumour effect of BCG. The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. Immune system cell subsets that have potential roles in BCG therapy include CD4(+) and CD8(+) lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. Bladder cancer cells are killed through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), and, to some degree, by the direct action of BCG. Several gaps still exist in our knowledge that should be addressed in future efforts to understand this biotherapy of cancer.Nature Reviews Urology 02/2014; · 4.79 Impact Factor
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ABSTRACT: Effective treatment of bladder cancer with bacillus Calmette-Guérin (BCG) depends on the induction of a T helper type (Th) 1 immune response. Interleukin (IL)-10 down-regulates the Th1 response and is associated with BCG failure. Here, we investigated whether blocking IL-10 signaling could enhance BCG-induced Th1 response and antitumor immunity in a murine orthotopic tumor model. Treatment with BCG and anti-IL-10 receptor 1 monoclonal antibody (anti-IL-10R1 mAb) increased the IFN-γ to IL-10 ratio in both splenocyte cultures and urine. Mice bearing luciferase-expressing MB49 (MB49-Luc) tumors were treated and followed for tumor growth by bioluminescent imaging, bladder weight and histology. Mice treated with PBS (Group 1), BCG plus control IgG1 (Group 2), or BCG plus anti-IL-10R1 mAb (Group 3) showed 0%, 6% and 22% tumor regression, respectively. The mean bladder weight of Group 3 mice was substantially less than those of Groups 1 and 2 mice. Remarkably, 36% of Group 1 and 53% of Group 2 mice but no Group 3 mice developed lung metastasis (p = 0.02). To investigate the mechanisms underlying the effect of combination therapy, splenocytes were stimulated with S12 peptide (serine mutation at codon 12 of the K-ras oncogene) known expressed in MB49-Luc cells. Induction of ras mutation-specific IFN-γ and cytotoxicity was observed in mice treated with combination therapy. These observations indicate that BCG in combination with anti-IL-10R1 mAb induces enhanced antitumor immunity that is protective against lung metastasis. Anti-IL-10R1 mAb demonstrates systemic effects and may prove useful in clinical practice for treating bladder cancer in high-risk patients.Clinical & Experimental Immunology 03/2014; · 3.28 Impact Factor