Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer
Abstract
Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both tumor infiltrating T-lymphocytes and tumor associated-macrophages were skewed towards TH2 in DOX-treated residual breast tumors; however, ESTA suppressed these changes. This study suggests that DOX treatment instigates de novo intratumoral infiltration of immune cells through E-selectin, and functional blockade of E-selectin may reduce residual tumor burden as well as metastasis through suppression of TH2 shift.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 19, 2020
- Source ID
- 10.3390/cancers12030725
Entities
People
- David E. Volk
- David G. Gorenstein
- Ganesh L. R. Lokesh
- Hallgeir Rui
- Hiroyasu Kameyama
- Inna Chervoneva
- Macall Leslie
- Nafis Hasan
- Natalie Hills
- Norihisa Ichimura
- Rachel Davis
- Roy Zhang
- Takemi Tanaka
- Yoshihiro Morita
- Yuji Kondo
Organizations
- American Cancer Society
- National Institutes of Health Clinical Center
- United States Department of Defense