Abstract
Background: Mast cells play a critical role in tumor-associated immune pathways. We aimed to determine whether the urinary mast cell mediators predict the immune response in patients with non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) immunotherapy.
Methods: Nineteen patients who have received immunotherapy due to NMIBC and 19 healthy participants were enrolled. Urine samples were collected to assay N-methylhistamine, histamine, and tryptase levels immediately before the first BCG instillation, immediately after the third and sixth instillations, and four weeks after the sixth instillation in patients with NMIBC and at a single visit in healthy participants. Cystoscopic examinations were performed on the patient with NMIBC at three-month intervals for two years. The changes in urinary markers due to BCC response, BCG instillation, and the presence of NMIBC were assessed.
Results: The average age was 56.1 ± 10.5 years in patients with NMIBC. Fourteen patients had high-grade Ta tumors, and 5 had high-grade T1 tumors. While 12 patients responded, 6 presented with recurrence and 1 with progression. There was no correlation between the levels of mast cell mediators and BCG response. The N-methylhistamine and histamine levels were increased significantly with the onset of immunotherapy, and N-methylhistamine levels were significantly decreased when immunotherapy was terminated. Pre-BCG estimated marginal means of N-methylhistamine were significantly higher in patients with NMIBC than healthy participants.
Conclusions: Our study is the first study to identify the changes in mast cell mediators with the onset of immunotherapy and with the presence of bladder cancer. However, these mediators were not found to predict the patients’ response to immunotherapy.
Keywords: BCG; bladder cancer; immunotherapy; mast cell; mediator.
Introduction
Bladder cancer is the 10th most common malignancy worldwide [1]. Approximately 70-80 % of patients present with non-muscle invasive bladder cancer (NMIBC) limited to the mucosa and lamina propria, and the remaining 20-30 % of patients present with muscle-invasive or metastatic disease [2]. Intravesical Bacillus Calmette-Guérin (BCG) is the most effective therapy for NMIBC [3]. Optimal improvements in recurrence and progression rates can be observed with intravesical BCG immunotherapy applied after transurethral resection (TUR). However, the rate of non-responders is seen up to 80 % in patients treated with BCG immunotherapy during long follow-up periods [4].
The immune microenvironment of bladder tissue plays a critical role in anti-tumor mechanisms. It is showed that different inflammatory cells infiltrate oncogenic tissue, including mast cells, neutrophils, macrophages, and lymphocytes, as a marker of the cancer-induced immune response [5]. Different mechanisms have been evaluated about interactions between bladder cancer, BCG immunotherapy, and immune response. After intravesical BCG immunotherapy, the antigen 85 complex adheres to the bladder wall through fibronectin and initiates an acute immune response in the bladder wall, but many questions remain unclear [6].
Clinical trials based on BCG induced acute immune response have examined T cells, cytokines, and macrophages. In these trials, bladder mast cell activity is thought to play a critical role in tumor pathways and angiogenesis [7]. The bladder mast cell contains many granules, each of which can secrete many immunoactive molecules. Of these mediators, elevated expression of IL 17, N-methylhistamine, histamine, and tryptase may accept as a marker of mast cell activation [7-9]. Although one study has confirmed the predictive value of IL-17+ mast cells in patients with NMIBC treated with BCG immunotherapy [7], there is no study in the literature investigating urinary N-methylhistamine, histamine, and tryptase levels. It is considered that the determination of the mast cell activation can contribute to the increase of our clinical approach to BCG immunotherapy. Furthermore, the determination of mast cell activation in patients with NMIBC who receive immunotherapy will benefit the development of mast cell-based new treatment approaches.
We aimed to investigate the changes in urinary mast cell mediators level in patients with NMIBC due to the instillation of BCG and the presence of NMIBC. In addition, we assessed the differences between responders and non-responders to immunotherapy in terms of urinary mast cell mediator levels.
Material and Methods