Exploring the Immunoresponse in Bladder Cancer Immunotherapy

Abstract

Bladder cancer (BC) represents a wide spectrum of diseases, ranging from recurrent non-invasive tumors to advanced stages that require intensive treatments. BC accounts for an estimated 500,000 new cases and 200,000 deaths worldwide every year. Understanding the biology of BC has changed how this disease is diagnosed and treated. Bladder cancer is highly immunogenic, involving innate and adaptive components of the immune system. Although little is still known of how immune cells respond to BC, immunotherapy with bacillus Calmette-Guérin (BCG) remains the gold standard in high-risk non-muscle invasive BC. For muscle-invasive BC and metastatic stages, immune checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have emerged as potent therapies, enhancing immune surveillance and tumor cell elimination. This review aims to unravel the immune responses involving innate and adaptive immune cells in BC that will contribute to establishing new and promising therapeutic options, while reviewing the immunotherapies currently in use in bladder cancer.

Keywords: BCG; bladder cancer; checkpoints; immune response; immunotherapy.

Figure 1

Immunological mechanisms of intravesical BCG treatment in bladder cancer: (A) Classification of BC according to the TNM staging system. CIS (carcinoma in situ) represents a non-muscle invasive bladder cancer (NMIBC) confined to the bladder lining; Ta, papillary NMIBC limited to the inner lining; T1, NMIBC that invades the subepithelial connective tissue without penetrating the muscle layer; T2, muscle-invasive bladder (MIBC) cancer; T3, MIBC that invades the perivesical tissue surrounding the bladder; and T4, advanced MIBC that invades surrounding structures such as the prostate, uterus, or pelvic wall. (B) NMIBC is treated with BCG. Upon instillation, BCG is taken up by bladder urothelial cells, antigen-presenting cells (APC), macrophages, and dendritic cells (DCs), leading to the release of pro-inflammatory cytokines and the activation of the immune response, including T and natural killer (NK) cells, which recognize and attack tumor cells. DCs express toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns (PAMPs), promoting the secretion of cytokines and the presentation of tumor antigens via the major histocompatibility complex (MHC) to CD4+ and CD8+ T lymphocytes, thus contributing to tumor eradication. BCG induces NK cell functional maturation, increasing the expression of CD56 and the release of proinflamatory cytokines, granzyme, and perforin, which contribute to the destruction of tumor cells. Understanding these mechanisms is vital for optimizing BCG therapy and improving outcomes for patients with bladder cancer.

Figure 2

Mechanisms of immune checkpoint blockade in cancer therapy. The adequate activation of T lymphocytes requires a primary specific signal delivered by the TCR/MHC interaction together with co-stimulatory signals mainly delivered by the CD28/CD80-CD86 interaction. In contrast, the interactions of CTLA-4/CD80-CD86, PD-1/PD-L1, NKG2A/HLA-E, or TIGIT/CD155 inhibit and regulate T cell activation and function. These inhibitory interactions can be blocked using immunotherapeutic monoclonal antibodies: anti-PD-1 (Nivolumab, Pembrolizumab), anti-PD-L1 (Atezolizumab, Avelumab, and Durvalumab), anti-CTLA-4 (Ipilimumab, Tremelimumab), anti-NKG2A (Monalizumab), or anti-TIGIT (Tiragolumab, Sacituzumab).