CCR4 Blockade Depletes Regulatory T Cells and Prolongs Survival in a Canine Model of Bladder Cancer

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. Tumorinfiltrating 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.

Retracted: Kinesin family member 3A stimulates cell proliferation, migration, and invasion of bladder cancer cells in vitro and in vivo

“…Originated from the bladder epithelial cells, bladder cancer is one of the most common malignant tumors of the urinary system with high morbidity and mortality, ranking the ninth in the world [1,2]. Bladder cancer was more common in male patients and older adults according to epidemiologic data [3].…”

A Role for Dogs in Advancing Cancer Immunotherapy Research

“…As another strategy to modify the TME, it was recently reported that blockade of CCR4 signaling with humanized antibodies could significantly deplete Tregs in a canine model of invasive bladder cancer (52). In that study, treatment with an anti-CCR4 antibody depleted Tregs in bladder tumor tissues in dogs, and was associated with sustained tumor regression, and prolonged survival.…”

Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges

“…The use of anti-CCR4 antibodies enables the removal of CCR4-expressing Treg that invades the cancer tissue and could reinforce the induction of cancer-specific T cells [160]. The percentage of cancer antigen-specific cytotoxic lymphocytes has been shown to increase after treatment with an anti-CCR4 antibody from the pretreatment level in patients with adult T cell leukemia [109].…”