Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer

Abstract

BackgroundTargeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, its efficacy in advanced prostate cancer remains unclear. Here, we showed the therapeutic efficacy of anti-Treg treatment in a canine model of advanced prostate cancer.MethodsWe used dogs with naturally occurring prostate cancer to study the molecular mechanism underlying Treg infiltration and the effect of anti-Treg treatment. Tumor-infiltrating Tregs was evaluated by immunohistochemistry, and the association with prognosis was examined in dogs with spontaneous prostate cancer. The molecular mechanism of Treg infiltration was explored by RNA sequencing and protein analyses. A non-randomized canine clinical trial was conducted to define the therapeutic potential of anti-Treg treatment for advanced prostate cancer. Human prostate cancer datasets were analyzed to compare gene expression in dogs and humans.ResultsTumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous prostate cancer. RNA sequencing and protein analyses showed a possible link between the CCL17–CCR4 pathway and the increase of tumor-infiltrating Tregs. Dogs with advanced prostate cancer responded to mogamulizumab, a monoclonal antibody targeting CCR4, with decreased circulating Tregs, improved survival, and low incidence of clinically relevant adverse events. Urinary CCL17 concentration and BRAFV595E mutation were independently predictive of the response to mogamulizumab. Analysis of a transcriptomic dataset of human prostate cancer showed that the CCL17–CCR4 axis correlated with Foxp3. In silico survival analyses revealed that high expression of CCL17 was associated with poor prognosis. Immunohistochemistry confirmed that tumor-infiltrating Tregs expressed CCR4 in human patients with prostate cancer.ConclusionsAnti-Treg treatment, through CCR4 blockade, may be a promising therapeutic approach for advanced prostate cancer in dogs and some population of human patients.

Comparative Evaluation of Tumor-Infiltrating Lymphocytes in Companion Animals: Immuno-Oncology as a Relevant Translational Model for Cancer Therapy

“…For canine prostate cancer, recent evidence shows that T and B lymphocytes are increased in the tissue and that intra-tumor CD3+ TILs and granzyme B+ cell estimation are correlated with survival [ 127 , 129 ]. Also, it has been shown that increased Tregs are associated with poor prognosis showing parallels with what is observed in human tumors [ 128 , 170 ].…”

Regulatory cells and the effect of cancer immunotherapy

“…It would also be interesting to study the effects of the timing and duration of such a Treg-targeting antibody treatment, to determine whether it is critical for the differential control of Treg and effector T cells, in other words, whether the longer the treatment, the more likely effector T cells are to be depleted, thereby hindering the generation of effective tumor immunity [ 18 , 35 ]. The anti-CCR4 antibody, mogamulizumab, has demonstrated an effective reduction in the frequency of effector Tregs that selectively augment the induction of tumor antigen-specific CD4 + and CD8 + T cells in vivo [ 36 , 37 ].…”

FOXP3+ regulatory T cells and the immune escape in solid tumours

“…Increased CCR4 expression is observed in activated Treg cells. Inhibition of CCR4 has been shown to reduce Treg cells accumulation, potentiate anti-tumour immune activity, sensitize tumours to PD-1 blockade and improve survival (53)(54)(55)(56). CCL5, activated by cancer FOXP3, is responsible for FOXP3 + Treg cells infiltration in pancreatic ductal adenocarcinoma (57).…”