OncoImmunology. 2012 Oct 1;1(7):1183-5

Blocking IL-10 Enhances Bacillus Calmette-Guérin Induced T Helper Type 1 Immune Responses and Anti-bladder Cancer Immunity.

Yi Luo

University of Iowa Carver College of Medicine, 375 Newton Rd., 3204 MERF, Iowa City, IA 52242, USA

 

ABSTRACT:

Proper induction of Th1 immunity is required for effective immunotherapy of bladder cancer with the bacillus Calmette-Guérin (BCG). Interleukin-10 (IL-10) downregulates the Th1 immune response and is associated with BCG therapy failure. We evaluated BCG plus IL-10 blocking antibodies and found that this combination therapy induces enhanced Th1 immune responses and anti-bladder cancer immunity in preclinical animal models.

PMID: 23170273

 

SUPPLEMENT:
Bladder cancer is a common malignant disease dominated by a T helper type (Th) 2 polarized immunopathologic response. Intravesical instillation of Mycobacterium bovis bacillus Calmette-Guérin (BCG) is widely used as the standard therapy for nonmuscle invasive bladder cancer (NMIBC). BCG therapy can shift the Th2 environment toward a Th1 milieu, leading to effective anti-bladder cancer immunity in the majority of patients. BCG therapy typically results in 50-60% effectiveness against small residual tumors and a 70-75% complete response rate for carcinoma in situ. However, BCG therapy is associated with 40-50% disease recurrence and a lack of therapeutic response in some patients. In addition, up to 90% of patients experience various side effects and occasionally even life-threatening complications such as sepsis. Therefore, the current BCG therapy is not optimal with respect to its efficacy and safety.

To improve BCG therapy, efforts have been made to enhance the induction of Th1 immune responses, since this response has been shown to be essential in BCG-mediated bladder cancer destruction. We have previously reported our investigations of BCG combined with Th1-stimulating cytokines such as IFN-α and IL-12 [1,2]. Additionally, we have investigated BCG in combination with IL-10 blocking agents for treating bladder cancer in animal models. IL-10 is classified as a Th2 cytokine and regulates growth and/or differentiation of various types of cells to control immune responses and tolerance in vivo. It has been known that IL-10 plays an inhibitory role in both bladder cancer immunosurveillance and BCG therapeutic efficacy, although it can promote antitumor responses in certain types of other cancers. Mice genetically deficient in IL-10 (IL-10-/-) developed a markedly increased local immune response, coinciding with increased therapeutic efficacy, after intravesical BCG treatment [3]. Our early studies also showed that absence of IL-10 abrogated either by systemic administration of an anti-IL-10 neutralizing monoclonal antibody (mAb) or by the use of IL-10-/- mice resulted in enhanced delayed-type hypersensitivity (DTH) responses that were associated with increased mononuclear cell infiltration and Th1 cytokine production (e.g. IFN-γ) in the BCG-treated bladders [4]. Under the condition of aggravated DTH responses, a significant enhancement in BCG-induced anti-bladder cancer immunity was also observed [4], suggesting that blocking IL-10 production and/or activity may provide therapeutic benefits for the BCG-based immunotherapy of bladder cancer.

We recently evaluated the effect of IL-10 blockage at the receptor level on BCG induction of Th1 immune responses and anti-bladder cancer immunity. Mice treated with intravesical BCG plus systemic administration of an anti-IL-10 receptor 1 (R1) mAb showed significantly increased IFN-γ mRNA and protein in the bladder and urine, respectively, in a dose-dependent manner [5]. Accordingly, mice implanted with bladder cancer cells and treated with BCG in combination with anti-IL-10R1 mAb showed substantially improved tumor-free and survival rates compared with control mice [5]. Studies further revealed that the combination therapy with a reduced dose (1/3 full-dose) of BCG could significantly prevent bladder cancer metastasis to the lung during an extended experimental period (no metastasis in mice treated with combination therapy vs. 36-53% of incidence in control mice) [6]. This observation suggests that BCG might be used at a reduced dose when combined with an IL-10 blocking agent to minimize BCG side effects while preserving or even enhancing BCG efficacy. The observed effects of anti-IL-10R1 mAb are presumably due to its direct inhibition on IL-10 signaling, leading to a Th1 enriched microenvironment in the bladder, a condition essential for the therapeutic control of bladder cancer by BCG. In supporting this, we have further observed that the combination therapy induces specific antitumor immune responses, i.e. ras mutation-specific IFN-γ production and cytotoxic T lymphocyte (CTL) activity, in the same animal model [6].

Taken together, our observations suggest that anti-IL-10R1 mAb might serve as an effective agent in the treatment of bladder cancer, particularly for high-risk patients with NMIBC, when combined with BCG. A humanized form of anti-IL-10R1 mAb warrants future investigation for BCG treatment of bladder cancer. As research continues, we anticipate that a new BCG therapy with improved efficacy and limited side effects will be available for bladder cancer, one of the most frequently occurring and most expensive cancers to treat.

Acknowledgment

This work was supported by Pfizer.

References

1. Luo Y, Chen X, Downs TM, DeWolf WC, O’Donnell MA. IFN-alpha 2B enhances Th1 cytokine responses in bladder cancer patients receiving Mycobacterium bovis bacillus Calmette-Guérin immunotherapy. J Immunol 1999; 162:2399-405.

2. O’Donnell MA, Luo Y, Chen X, Szilvasi A, Hunter SE, Clinton SK. Role of IL-12 in the induction and potentiation of IFN-γ in response to bacillus Calmette-Guérin. J Immunol 1999; 163:4246-52.

3. Riemensberger J, Böhle A, Brandau S. IFN-gamma and IL-12 but not IL-10 are required for local tumour surveillance in a syngeneic model of orthotopic bladder cancer. Clin Exp Immunol 2002; 127:20-6.

4. Nadler R, Luo Y, Zhao W, Ritchey JK, Austin JC, Cohen MB, O’Donnell MA, Ratliff TL. Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity. Clin Exp Immunol 2003; 131:206-16.

5. Bockholt NA, Knudson MJ, Henning JR, Maymi JL, Weady P, Smith GJ III, Eisenbraun MD, Fraser JD, O’Donnell MA, Luo Y. Anti-IL-10R1 monoclonal antibody enhances BCG-induced TH1 immune responses and antitumor immunity in a mouse orthotopic model of bladder cancer. J Urol 2012; 2228-35.

6. Newton MR, Askeland EJ, Andersen ED, Chehval VA, Wang X, Askeland R, O’Donnell MA, Luo Y. Anti-interleukin-10R1 monoclonal antibody in combination with BCG is protective against bladder cancer metastasis in a murine orthotopic tumor model and demonstrates systemic antitumor immunity. Clin Exp Immunol 2014 (in press).

 

Contact Information

Dr. Yi Luo

University of Iowa Carver College of Medicine

375 Newton Rd., 3204 MERF, Iowa City, IA 52242, USA

Tel: 319-335-9835

Email: yi-luo@uiowa.edu

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