Institut Pasteur; Unité d'Epidémiologie des Maladies Emergentes; Paris, France.
Oncoimmunology. 2012 Jan 1;1(1):9-17. doi: 10.4161/onci.1.1.17884.
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.
膀胱非肌肉浸润性癌的治疗是肿瘤免疫成功的少数几个例子之一。每周六次膀胱内灌注卡介苗（BCG），通常随后进行维持治疗，可导致多达 50-70%的临床反应。目前的模型表明，作用机制涉及非特异性激活先天效应细胞，这些细胞可能在没有抗原特异性反应的情况下发挥作用。例如，最近的证据表明，BCG 激活的中性粒细胞具有抗肿瘤潜力。此外，每周 BCG 治疗会导致先天免疫细胞大量涌入（尿液中 107-108 PMN/ml）的初免-加强模式。根据体内数据校准，我们估计每次灌注的中性粒细胞脱颗粒数约为 106-107，足以潜在消除约 106 个残留肿瘤细胞。此外，中性粒细胞以及其他先天效应细胞在其靶向作用上没有选择性-因此脱颗粒和/或细胞因子产生可能会影响周围细胞。为了确定这些观察到的情况是否可以解释临床上有效的肿瘤免疫，我们建立了一个反映接受 BCG 治疗的患者早期事件和组织调理的数学模型。该模型纳入了肿瘤生长、BCG 灌注以及观察到的先天免疫反应初免-加强模式的关键特征。模型校准确定，每个先天效应细胞必须杀死 90-95%的旁观者细胞，才能实现预期的 50-70%的临床反应。这一预测通过实证和实验进行了评估，发现远远超过了先天免疫系统的能力。因此，我们得出结论，先天免疫系统本身无法消除肿瘤细胞。我们推断，免疫反应的其他方面（例如，抗原特异性淋巴细胞）对 BCG 免疫治疗的成功起到了决定性的作用。
