Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer

Yoshihiro Morita; Macall Leslie; Hiroyasu Kameyama; Ganesh L R Lokesh; Norihisa Ichimura; Rachel Davis; Natalie Hills; Nafis Hasan; Roy Zhang; Yuji Kondo; David G Gorenstein; David E Volk; Inna Chervoneva; Hallgeir Rui; Takemi Tanaka

doi:10.3390/cancers12030725

Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer

Cancers (Basel). 2020 Mar 19;12(3):725. doi: 10.3390/cancers12030725.

Authors

Affiliations

¹ Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK 73104, USA.
² McGovern Medical School, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, TX 77030, USA.
³ School of Medicine, University of Oklahoma Health Sciences Center, 800 Stanton L. Young Blvd., Oklahoma City, OK 73104, USA.
⁴ Department of Pharmaceutical Sciences, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA.
⁵ Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, 940 SL Young Blvd, Oklahoma City, OK 73104, USA.
⁶ Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 NE. 13th, Oklahoma City, OK 73104, USA.
⁷ AM Biotechnologies, LLC, 12521 Gulf Freeway, Houston, TX 77034, USA.
⁸ Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1015 Chestnut St., Philadelphia, PA 19107, USA.
⁹ Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.

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 T_H2 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 T_H2 shift.

Keywords: E-selectin; aptamer; doxorubicin; tumor-associated-macrophages.

Abstract

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