CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors

Abstract

Over half of breast cancer related deaths are due to recurrence five 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.

Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor Progression

“…Driven the fact that macrophages could be recruited to in ammatory regions by chemokines, including CCL2 [26] and CCL5 [17], we supposed that macrophages surrounded by adipocytes were recruited by CCL2 and CCL5 to adipose tissue. Of 145 breast cancer specimens in our study, we found that the chemokines, both CCL2 and CCL5, overexpressed around the adipose tissues (Fig.…”

“…Meanwhile, CCL5 could recruit CCR5-overexpressing macrophages, subsequently which depose collagens in residual tumors to drive tumor recurrence [17]. However, whether the expressions of CCL2 and CCL5 are elevated in tumor-associated adipose microenvironment, and repolarize the residual macrophages is less well characterized.…”

Tamoxifen Suppresses Brain Metastasis of Estrogen Receptor-deficient Breast Cancer by Skewing Microglia Polarization and Enhancing Their Immune Functions

“…The CCL5 and its receptor CCR5 have been detected in hematological malignancies and lymphomas. The interaction of CCL5 and CCR5 has been shown to promote tumor development by multiple mechanisms including acting as growth factors [65], enhancing migration and invasiveness [66], stimulating angiogenesis [67], and recruitment of macrophage [68]. Furthermore, knockdown or knockout of CCL5 in tumor cells was shown to suppress metastatic capability in vivo and in vitro of 4T1 breast cancer model [65,69].…”

Tamoxifen suppresses brain metastasis of estrogen receptor-deficient breast cancer by skewing microglia polarization and enhancing their immune functions

“…The CCL5 and its receptor CCR5 have been detected in hematological malignancies and lymphomas. The interaction of CCL5 and CCR5 has been shown to promote tumor development by multiple mechanisms including acting as growth factors [76], enhancing migration and invasiveness [77], stimulating angiogenesis [78], and recruitment of macrophage [79]. Furthermore, knockdown or knockout of CCL5 in tumor cells was shown to suppress metastatic capability in vivo and in vitro of 4T1 breast cancer model [76,80].…”