Abstract
Regulatory T-cell (Treg) infiltration can be targeted as a cancer immunotherapy. Here, we describe therapeutic efficacy of this strategy in a canine model of bladder cancer. We used dogs with naturally occurring bladder cancer to study the molecular mechanism of Treg infiltration into bladder cancer tissues and the effect of anti-Treg treatment. Tumor-infiltrating Tregs were evaluated by immunohistochemistry, and their association with prognosis was examined in dogs with bladder cancer. The molecular mechanism of Treg infiltration was explored by RNA sequencing and protein analyses. Murine xenograft experiments and canine studies were used to explore the therapeutic potential of anti-Treg treatment for bladder cancer. We found that tumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous bladder cancer. Treg infiltration was caused by interaction between the tumor-producing chemokine CCL17 and the receptor CCR4 expressed on Tregs. CCR4 blockade inhibited tumor growth and Treg infiltration into the tissues in a xenograft mouse model. Dogs with spontaneous bladder cancer responded to anti-CCR4 treatment with improved survival and low incidence of clinically relevant toxicities. In human patients with bladder cancer, immunohistochemistry showed that tumor-infiltrating Tregs expressed CCR4. Thus, anti-CCR4 treatment may be a rational approach to test in clinical trials for human patients with bladder cancer.
Highlights
Bladder cancer is a prevalent and aggressive malignancy related to nearly 168,000 deaths annually worldwide [1]
Tumor-infiltrating Tregs correlate with poor prognosis in canine bladder cancer
CCL17 expression is elevated in canine bladder cancer To identify molecules guiding Treg infiltration in canine bladder cancer, we explored differentially expressed genes (DEGs) of chemoattractants for Tregs using a previously generated RNA sequencing (RNA-seq) data set [20]
Summary
Bladder cancer is a prevalent and aggressive malignancy related to nearly 168,000 deaths annually worldwide [1]. This cancer is variegated and histologically categorized into two types: The lowgrade, superficial type, is more prevalent ($70%) and is related to a favorable prognosis. The high-grade, muscle-invasive type, is less prevalent ($30%) and poses a high mortality risk due to metastasis [2]. Platinum-based chemotherapy is typically used for advanced disease, patient outcomes are poor, with overall survival ranging from 9 to 15 months [3, 4]. The 5-year survival rate is approximately 5% in the metastatic setting.
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