The Laws of Attraction: Chemokines as Critical Mediators in Cancer Progression and Immunotherapy Response in Bladder Cancer.

Bladder cancer (BCa) is a prevalent urogenital malignancy, characterized by a myriad of genetic and environmental risk factors that drive its progression. Approximately 75% of bladder tumors are non-muscle-invasive at diagnosis. For such cases, bladder preservation is often feasible with intravesical chemotherapy or immunotherapy. However, the high recurrence rates associated with these tumors necessitate multiple cystoscopic examinations and biopsies, leading to significant financial burden and morbidity. Despite bladder tumors exhibiting one of the highest cancer mutational loads, which typically correlates with improved responses to immunotherapy, challenges persist. The tumor microenvironment serves as a nexus for interactions between tumor cells and the immune system, wherein chemokines and chemokine receptors orchestrate the recruitment of immune cells. This review addresses existing gaps in our understanding of chemokine dynamics in BCa by elucidating the specific roles of key chemokines in shaping the immune landscape of the tumor microenvironment (TME). We explore how dysregulation of chemokine signaling pathways contributes to the recruitment of immunosuppressive cell populations, such as Tregs and monocytes, leading to an unfavorable immune response. Additionally, we highlight the potential of these chemokines as predictive biomarkers for tumor progression and treatment outcomes, emphasizing their role in informing personalized immunotherapeutic strategies. By integrating insights into chemokine networks and their implications for immune cell dynamics, this review seeks to provide a comprehensive understanding of the interplay between chemokines and the immune microenvironment in BCa. Furthermore, we discuss the potential of targeting these chemokine pathways as innovative immunotherapeutic strategies, paving the way for enhanced treatment responses and improved patient outcomes.

Perioperative Immune Checkpoint Blockade for Muscle-Invasive and Metastatic Bladder Cancer.

Checkpoint inhibitors offer promise in treating muscle-invasive and metastatic bladder cancer, but the optimal timing of their administration-neoadjuvant or adjuvant-remains unclear. To determine the efficacy of combining checkpoint inhibition with standard cisplatin-based chemotherapy, we conducted a phase II trial of neoadjuvant anti-PD-1 (αPD-1) and anti-CTLA-4 (αCTLA-4), in combination with cisplatin-gemcitabine, for patients with muscle-invasive bladder cancer prior to radical cystectomy. In addition, a novel murine model of spontaneous metastatic bladder cancer was used to compare the efficacy of neoadjuvant versus adjuvant anti-PD-L1 (αPD-L1) treatment. The clinical trial was closed prematurely due to the industry's withdrawal of drug provision. Adverse events were observed in all patients; however, serious adverse events were not observed in any patient. A complete pathologic response was observed in 50% of the 4 patients enrolled. Response to treatment was significantly associated with elevated urinary T cells including CD8+ and IFNγ+ CD4+ T cells, suggesting potential reinforcement of immune responses by neoadjuvant αPD-1 and αCTLA-4 against bladder tumor cells. These findings suggest that combining chemotherapy and immunotherapy in the neoadjuvant setting could be safe. However, the complete response rate of this four-drug regimen was modest and emphasizes the need for randomized controlled trials to properly assess immunotherapy efficacy in the neoadjuvant setting. In corresponding murine studies, the MB49-met model consistently displayed widespread metastasis, including tumor growth in the lungs, liver, and bowel mesentery, within 20 days of subcutaneous transplantation. Mice receiving surgery plus neoadjuvant αPD-L1 or adjuvant αPD-L1 exhibited improved survival compared to those receiving only αPD-L1. However, no significant difference in survival was observed between the neoadjuvant and adjuvant αPD-L1 cohorts. Furthermore, the timing of neoadjuvant therapy administration (early vs. late) did not significantly impact survival. This study highlights the potential of perioperative immunotherapy in the treatment of locally advanced and metastatic bladder cancer.

Innate Lymphoid Cells in Bladder Cancer: From Mechanisms of Action to Immune Therapies.

Bladder tumors have a high mutational burden and tend to be responsive to immune therapies; however, response rates remain modest. To date, immunotherapy in bladder cancer has largely focused on enhancing T-cell immune responses in the bladder tumor microenvironment. It is anticipated that other immune cells, including innate lymphoid cells (ILC), which play an important role in bladder oncogenesis and tumor suppression, could be targeted to improve response to existing therapies. ILCs are classified into five groups: natural killer cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells. ILCs are pleiotropic and play dual and sometimes paradoxical roles in cancer development and progression. Here, a comprehensive discussion of the current knowledge and recent advancements in understanding the role of ILCs in bladder cancer is provided. We discuss the multifaceted roles that ILCs play in bladder immune surveillance, tumor protection, and immunopathology of bladder cancer. This review provides a rationale for targeting ILCs in bladder cancer, which is relevant for other solid tumors.