Burns Caitlin P, Parker Jacob M, Schaap Dylan M, Wakefield Mark R, Fang Yujiang
Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, West Des Moines, IA 50266, USA.
Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA.
Cancers (Basel). 2025 Mar 28;17(7):1135. doi: 10.3390/cancers17071135.
Non-muscle invasive bladder cancer (NMIBC) represents a significant clinical challenge due to its high recurrence rate and need for frequent monitoring. The current treatment modality is bacillus Calmette-Guérin (BCG) therapy combined with chemotherapy after transurethral resection of the bladder tumor (TURBT), which is highly effective in most patients. Yet, the cancer becomes resistant to these treatments in 30-40% of patients, necessitating the need for new treatment modalities. In the cancer world, the development of immune checkpoint inhibitors that target molecules, such as programmed cell death protein-1 (PD-1), its ligand, PD-L1, and Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), have revolutionized the treatment of many cancer types. PD-1/PD-L1 and CTLA-4 are shown to be upregulated in NMIBC in certain circumstances. PD-1/PD-L1 interactions play a role in immune evasion by suppressing T cell activity within the tumor microenvironment (TME), while the binding of CTLA-4 on T cells leads to downregulation of the immune response, making these pathways potential immunotherapeutic targets in NMIBC. This review seeks to understand the role of these therapies in treating NMIBC. We explore the cellular and non-cellular immune landscape in the TME of NMIBC, including Tregs, T effector cells, macrophages, B cells, and relevant cytokines. We also discuss the biological role of PD-1/PD-L1 and CTLA-4 while covering the rationale for these immunotherapies in NMIBC. Finally, we cover key clinical trials that have studied these treatments in NMIBC clinically. Such a study will be helpful for urologists and oncologists to manage patients with NMIBC more effectively.
非肌层浸润性膀胱癌（NMIBC）因其高复发率和需要频繁监测而成为一项重大的临床挑战。当前的治疗方式是在经尿道膀胱肿瘤切除术（TURBT）后采用卡介苗（BCG）疗法联合化疗，这对大多数患者非常有效。然而，30%-40%的患者会对这些治疗产生耐药性，因此需要新的治疗方式。在癌症领域，针对程序性细胞死亡蛋白-1（PD-1）、其配体PD-L1以及细胞毒性T淋巴细胞相关蛋白4（CTLA-4）等分子的免疫检查点抑制剂的开发，彻底改变了许多癌症类型的治疗方式。在某些情况下，PD-1/PD-L1和CTLA-4在NMIBC中被证明上调。PD-1/PD-L1相互作用通过抑制肿瘤微环境（TME）中的T细胞活性在免疫逃逸中发挥作用，而CTLA-4在T细胞上的结合导致免疫反应下调，使这些途径成为NMIBC潜在的免疫治疗靶点。本综述旨在了解这些疗法在治疗NMIBC中的作用。我们探讨了NMIBC的TME中的细胞和非细胞免疫格局，包括调节性T细胞（Tregs）、效应T细胞、巨噬细胞、B细胞和相关细胞因子。我们还讨论了PD-1/PD-L1和CTLA-4的生物学作用，同时阐述了这些免疫疗法在NMIBC中的理论依据。最后，我们涵盖了在临床上研究这些治疗方法的关键临床试验。这样的研究将有助于泌尿外科医生和肿瘤内科医生更有效地管理NMIBC患者。
