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Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response.

ABSTRACT: Treatment for non-muscle invasive carcinoma of the bladder represents one of the few examples of successful tumor immunity. Six weekly intravesical instillations of Bacillus Calmette-Guerin (BCG), often followed by maintenance schedule, result in up to 50-70% clinical response. Current models suggest that the mechanism of action involves the non-specific activation of innate effector cells, which may be capable of acting in the absence of an antigen-specific response. For example, recent evidence suggests that BCG-activated neutrophils possess anti-tumor potential. Moreover, weekly BCG treatment results in a prime-boost pattern with massive influx of innate immune cells (107-108 PMN/ml urine). Calibrating in vivo data, we estimate that the number of neutrophil degranulations per instillation is approximately 106-107, more than sufficient to potentially eliminate ~106 residual tumor cells. Furthermore, neutrophils, as well as other innate effector cells are not selective in their targeting-thus surrounding cells may be influenced by degranulation and / or cytokine production. To establish if these observed conditions could account for clinically effective tumor immunity, we built a mathematical model reflecting the early events and tissue conditioning in patients undergoing BCG therapy. The model incorporates key features of tumor growth, BCG instillations and the observed prime / boost pattern of the innate immune response. Model calibration established that each innate effector cell must kill 90-95 bystander cells for achieving the expected 50-70% clinical response. This prediction was evaluated both empirically and experimentally and found to vastly exceed the capacity of the innate immune system. We therefore conclude that the innate immune system alone is unable to eliminate the tumor cells. We infer that other aspects of the immune response (e.g., antigen-specific lymphocytes) decisively contribute to the success of BCG immunotherapy.

SUBMITTER: Breban R

PROVIDER: S-EPMC3376955 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response.

Breban Romulus R Bisiaux Aurelie A Biot Claire C Rentsch Cyrill C Bousso Philippe P Albert Matthew L ML

Oncoimmunology 20120101 1

Treatment for non-muscle invasive carcinoma of the bladder represents one of the few examples of successful tumor immunity. Six weekly intravesical instillations of Bacillus Calmette-Guerin (BCG), often followed by maintenance schedule, result in up to 50-70% clinical response. Current models suggest that the mechanism of action involves the non-specific activation of innate effector cells, which may be capable of acting in the absence of an antigen-specific response. For example, recent evidenc ...[more]

PMID: 22720207

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Project description:Background: Bladder cancer (BC) is a leading cause of death from malignancy, with significant heterogeneity in the immunotherapeutic responsiveness of advanced status. Pyroptosis, a newly discovered inflammatory programmed cell death, is confirmed to play an indispensable role in tumorigenesis and anti-tumor activity. However, the effect of pyroptosis on the tumor-immune landscape remodeling and immunotherapy in BC remains elusive. Methods: We comprehensively evaluated the mRNA expression and genomic alterations of 33 pyroptosis-related genes (PRGs) in BC and evaluated the patterns of pyroptosis in publicly available BC datasets. An unsupervised clustering method was used to classify patients into distinct patterns. Then, we established a pyroptosis-related signature score (PS-score) model to quantify the pyroptosis-related patterns of individual BC patients using principal component analysis. Furthermore, we correlated the patterns with the immune landscape and response efficacy of immunotherapy. Results: Two pyroptosis-related patterns were identified in BC, and distinct patterns showed various immune characteristics. Patterns with a high expression level of PRGs exhibited a survival advantage and showed higher infiltration of cytotoxic lymphocytes. Tumors with a low PS-score were characterized by high tumor-infiltrating lymphocytes and considered "hot." Further analysis revealed that the PS-score was an independent prognostic factor and could predict the response to immunotherapy for patients with advanced BC. We found a significant positive association between AHNAK2, AHNAK nucleoprotein 2, expression, and PS-score. Functional assays showed that AHNAK2 knockdown was correlated with attenuated invasive ability. Conclusion: This work comprehensively demonstrated the potential function of pyroptosis-related patterns in the bladder tumor-immune landscape and identified their therapeutic liability in immunotherapy. Our study enhanced our understanding of the immune landscape and provided a new approach toward more effective immunotherapy strategies.

Dataset Information

Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response.

Publications

Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response.

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