CCR4 blockade leads to clinical activity and prolongs survival in a canine model of advanced prostate cancer

Abstract

Targeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, the efficacy of this strategy in advanced prostate cancer remains unclear. Here, we describe the therapeutic efficacy of this strategy in a canine model of advanced prostate cancer. We used dogs with naturally occurring prostate cancer to study the molecular mechanism underlying Treg infiltration into tumor tissues and the effect of anti-Treg treatment. We found that tumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous prostate cancer. RNA sequencing and protein analyses showed that Treg infiltration was mediated by interaction between the tumor-producing chemokine, CCL17, and the receptor CCR4 expressed on Tregs. Dogs with advanced prostate cancer responded to mogamulizumab, a monoclonal antibody targeting CCR4, with improved survival and low incidence of clinically relevant adverse events. Exploratory analyses showed urinary CCL17 concentration and BRAFV595E mutation to be independently predictive of the response to mogamulizumab. Analysis of a publicly available transcriptomic dataset of human prostate cancer showed that the CCL17/CCR4 axis correlated with the Treg marker, Foxp3. In silico survival analyses showed that high expression of CCL17 was associated with poor prognosis. Immunohistochemistry confirmed that tumor-infiltrating Tregs expressed CCR4 in human patients with prostate cancer. These findings suggest that anti-Treg treatment through the blocking of CCR4 is a promising therapeutic approach for advanced prostate cancer.

Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

“…Importantly, a canine clinical trial revealed that anti-CCR4 treatment with Mogamulizumab improved the survival rate while exhibiting a low rate of clinically relevant adverse effects, providing rationale for the translation of CCR4 blockade therapy to human patients with bladder cancer [189]. The same author reported that the CCR4 blockade led to clinical activity and prolonged survival in a canine model of advanced prostate cancer [190]. Altogether, these works confirmed the feasibility and clinical efficacy of these therapies in the veterinary setting and validated the potential of the canine model for the translation of chemokine-related immune therapies.…”