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