Department of Urology, University of Iowa Hospitals & Clinics, Iowa City, IA 52242, USA.
Department of Urology, Cochin Hospital, Assistance Publique-Hopitaux de Paris, 75014 Paris, France.
Front Biosci (Landmark Ed). 2024 Aug 21;29(8):295. doi: 10.31083/j.fbl2908295.
While more than four decades have elapsed since intravesical Bacillus Calmette-Guérin (BCG) was first used to manage non-muscle invasive bladder cancer (NMIBC), its precise mechanism of anti-tumor action remains incompletely understood. Besides the classic theory that BCG induces local (within the bladder) innate and adaptive immunity through interaction with multiple immune cells, three new concepts have emerged in the past few years that help explain the variable response to BCG therapy between patients. First, BCG has been found to directly interact and become internalized within cancer cells, inducing them to act as antigen-presenting cells (APCs) for T-cells while releasing multiple cytokines. Second, BCG has a direct cytotoxic effect on cancer cells by inducing apoptosis through caspase-dependent pathways, causing cell cycle arrest, releasing proteases from mitochondria, and inducing reactive oxygen species-mediated cell injury. Third, BCG can increase the expression of programmed death ligand 1 (PD-L1) on both cancer and infiltrating inflammatory cells to impair the cell-mediated immune response. Current data has shown that high-grade recurrence after BCG therapy is related to CD8 T-cell anergy or 'exhaustion'. High-field cancerization and subsequently higher neoantigen presentation to T-cells are also associated with this anergy. This may explain why BCG therapy stops working after a certain time in many patients. This review summarizes the detailed immunologic reactions associated with BCG therapy and the role of immune cell subsets in this process. Moreover, this improved mechanistic understanding suggests new strategies for enhancing the anti-tumor efficacy of BCG for future clinical benefit.
自膀胱内卡介苗（BCG）首次用于治疗非肌肉浸润性膀胱癌（NMIBC）以来，已经过去了四十多年，但它的确切抗肿瘤作用机制仍不完全清楚。除了 BCG 通过与多种免疫细胞相互作用在膀胱内诱导局部（膀胱内）先天和适应性免疫的经典理论外，过去几年出现了三个新概念，有助于解释患者之间对 BCG 治疗的反应差异。首先，已经发现 BCG 可以直接相互作用并被内化在癌细胞内，使其充当 T 细胞的抗原呈递细胞（APC），同时释放多种细胞因子。其次，BCG 通过 caspase 依赖性途径诱导细胞凋亡对癌细胞具有直接的细胞毒性作用，导致细胞周期停滞，从线粒体释放蛋白酶，并诱导活性氧介导的细胞损伤。第三，BCG 可以增加癌细胞和浸润性炎症细胞上程序性死亡配体 1（PD-L1）的表达，从而损害细胞介导的免疫反应。目前的数据表明，BCG 治疗后的高级别复发与 CD8 T 细胞无能或“耗竭”有关。高场癌变和随后更高的新抗原呈递给 T 细胞也与这种无能有关。这也许可以解释为什么在许多患者中，BCG 治疗在一段时间后会失效。本文综述了与 BCG 治疗相关的详细免疫反应以及免疫细胞亚群在该过程中的作用。此外，这种对机制的深入理解为未来的临床获益提出了增强 BCG 抗肿瘤疗效的新策略。
