Oestrogen deprivation induces chemokine production and immune cell recruitment in in vitro and in vivo models of oestrogen receptor-positive breast cancer

Abstract

Background Oestrogen receptor-positive (ER+) breast cancer is commonly treated using endocrine therapies such as aromatase inhibitors which block synthesis of oestradiol, but the influence of this therapy on the immune composition of breast tumours has not been fully explored. Previous findings suggest that tumour infiltrating lymphocytes and immune-related gene expression may be altered by treatment with aromatase inhibitors. However, whether these changes are a direct result of impacts on the host immune system or mediated through tumour cells is not known. We aimed to investigate the effect of oestrogen deprivation on the expression of chemokines and immune infiltration in vitro and in an ER+ immunocompetent mouse model. Methods RT-qPCR and a bead-based Bioplex system were used to investigate the expression of chemokines in MCF-7 breast cancer cells deprived of oestrogen. A migration assay and flow cytometry were used to measure the migration of human peripheral blood mononuclear cells (PBMCs) to MCF-7 cells grown without the main biologically active oestrogen, oestradiol. Using flow cytometry and immunohistochemistry, we examined the immune cell infiltrate into tumours created by injecting SSM3 ER+ breast cancer cells into wild-type, immunocompetent 129/SvEv mice. Results This study demonstrates that oestrogen deprivation increases breast cancer secretion of TNF, CCL5, IL-6, IL-8, and CCL22 and alters total human peripheral blood mononuclear cell migration in an in vitro assay. Oestrogen deprivation of breast cancer cells increases migration of CD4+ T cells and decreases migration of CD11c+ and CD14+ PBMC towards cancer cells. PBMC migration towards breast cancer cells can be reduced by treatment with the non-steroidal anti-inflammatory drugs, aspirin and celecoxib. Treatment with endocrine therapy using the aromatase inhibitor letrozole increases CD4+ T cell infiltration into ER+ breast cancer tumours in immune competent mice. Conclusions These results suggest that anti-oestrogen treatment of ER+ breast cancer cells can alter cytokine production and immune cells in the area surrounding the cancer cells. These findings may have implications for the combination and timing of anti-oestrogen therapies with other therapies.

Estrogen-induced immune changes within the normal mammary gland

“…If specific immune cell populations are blocked, normal breast development is impacted 48 , 49 . Supporting our work with endocrine therapy and oophorectomy, estrogen deprived BCa cells with increased levels of chemokines compared to non-deprived cells, enhance immune cell migration 50 . Using qPCR on epithelial cells isolated from treated mammary glands we found that transcript for Csf2, Interferon-γ (Ifn-γ) and Ccl5 were increased by estrogen exposure.…”

Factors Affecting the Quality of Life of Breast Cancer Patients

“…Persistent physical symptoms can increase fatigue and hinder patients' return to normal life, thereby reducing their quality of life. Therefore, continuous and systematic symptom management is necessary for breast cancer patients to adapt to normal life [30].…”

Breast Cancer Immune Landscape: Interplay Between Systemic and Local Immunity

“…[71] Similar to other immune cells, CD4 + T-cells are attracted to TME of BC patients by chemokines secreted by the tumor: TNF-𝛼, CCL5, CCL18, CCL22, IL-6, IL-8, IL-13, etc. [46,90,91] BC patients are characterized by high levels of CCL18, which recruits Th0 to TME by binding to the membraneassociated phosphatidylinositol transfer protein 3 (PITPNM3) receptor on CD4 + T-cells. [90,92] On the other hand, Tregs recruitment to TME requires the secretion of CCL1, CCL2, CCL5, CCL28, CXCL12, IL-35, and CXCR4.…”