CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors

Abstract

Over half of breast-cancer-related deaths are due to recurrence 5 or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.

eLife digest

Breast cancer is the second-leading cause of cancer-related deaths in women. Recurrence of breast-cancer five or more years after initial diagnosis and treatment causes more than half of these deaths. This suggests that some tumor cells survived treatment and persisted undetected. These residual tumor cells may not grow for years and are often surrounded by other cells, including immune system cells. What role these surrounding immune cells play in triggering future growth of these residual tumor cells is not clear.

Many breast cancer patients receive chemotherapy, which kills all quickly dividing cells. Targeted therapies, which block signals necessary for cancer cell growth, are also used often. More recently, scientists have developed treatments that use a patients own immune system to fight off cancer. Scientists are currently studying whether combining these immunotherapies with chemotherapy or targeted therapies increases the likelihood of eliminating cancer. Learning more about the role surrounding immune cells play in allowing residual tumor cells to persist and regrow is important to understanding how to treat cancer more successfully and prevent recurrence.

Now, Walens et al. show that immune cells called macrophages supply residual breast cancer cells in mice with a protein called collagen that they need to grow. In the experiments, mice with an aggressive form of breast cancer called Her2 received targeted cancer therapy. After the treatment, tumor cells in the mice released small molecules called cytokines that attract immune system cells. Levels of one cytokine called CCL5 rose after treatment and remained high in residual tumors in the mice. The experiments also revealed that CCL5 levels were high in residual breast cancer tumors collected from women.

This shows that high levels of CCL5 appear to shorten the amount of time between tumor treatment and recurrence because CCL5 attracts macrophages that deposit collagen in the residual tumors. Scientists believe collagen promotes tumor growth because recurrent tumors have high levels of collagen and breast cancer patients with high levels of collagen in their tumors often have worse outcomes. Treatments that prevent or block the release of CCL5 or that stop macrophages from supplying the residual tumor cells with collagen may help prevent recurrence.