CCR5+ regulatory T cells induced by metastatic breast carcinomas migrate toward a gradient of CCL8 and accumulate in metastatic lung tissue (TUM9P.1016)

Under homeostatic conditions, regulatory T cells (Tregs) mediate peripheral tolerance and prevent autoimmunity. Despite their crucial role in the regulation of immunity toward innocuous antigens, Tregs may also contribute to the growth and metastasis of breast cancer by suppressing anti-tumor immune responses. We are interested in developing therapies to inhibit intratumoral Treg infiltration to decrease the growth of primary and metastatic tumors. Using mammary carcinomas syngenic to BALB/c mice, we identified elevated levels of CCR5 + Tregs in the primary tumour and metastatic lungs relative to naive control tissues. Interestingly, we observed that C-C chemokine receptor type 5 (CCR5) is highly and selectively expressed by Tregs in metastatic lungs relative to other immune cell populations. CCR5 + Tregs largely co-express CTLA-4 and CD103, indicating a suppressive phenotype. The production of CCL8, an endogenous ligand of CCR5, was increased in the tumour and lungs, and CCL8-mediated migration of Tregs ex vivo was inhibited by the CCR5 antagonist Maraviroc. These data suggest that targeting CCR5 or CCL8 may be a viable therapeutic strategy to inhibit Treg accumulation during tumour progression to decrease metastatic tumour growth. Currently, there is a paucity of research involving the role of CCR5 + Tregs in tumour progression. We anticipate that this work will advance the generation of targeted, immune-based therapeutics for the treatment of metastatic breast cancer.