Non-depleting reformation of immunosuppressive myeloid cells to broaden the application of anti-PD therapy

• Published in: Nanoscale Vol. 13; no. 8; pp. 442 - 4431
• Main Authors: Peng, Si-Yuan, Chen, Lei, Deng, Rong-Hui, Li, Hao, Liu, Xin-Hua, Zheng, Di-Wei, Wu, Cong-Cong, Liu, Chuan-Jun, Sun, Zhi-Jun, Zhang, Xian-Zheng
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 04.03.2021
• Subjects: Animals; Antibodies; Antigens; Cell Line, Tumor; Depletion; Immunotherapy; Lymphocytes; Macrophages; Mice; Myeloid Cells; Myeloid-Derived Suppressor Cells; Retinoic acid
• ISSN: 2040-3364; 2040-3372; 2040-3372
• DOI: 10.1039/d1nr00830g

Traditional methods of depleting tumor-associated myeloid cells via chemotherapy can easily lead to the re-recruitment of them, eventually resulting in chemo-resistance and presenting obstacles in immunotherapy. Herein, we report a nano-educator (NE) that when loaded with all trans retinoic acid (ATRA) and anti-PD-1 antibodies (aPD-1) instructs myeloid cells to assist T cells towards revitalizing anti-PD-1 therapy. In vivo , ATRA converts myeloid-derived suppressor cells (MDSCs) into dendritic cells (DCs), which are essential for anti-PD-1 therapy, while intervening in the polarization of macrophages. Furthermore, aPD-1-armed T cells reboot anti-tumor immunity after suppression relief, which exposes tumor-specific antigens and in turn promotes the maturation of transformed DCs. The nano-platform provides shelter for vulnerable immunomodulatory agents and durable drug release to stimulate intensive immune modulation. We established three types of tumor-bearing mice models with different myeloid cell contents to show the spatiotemporal complementarity of ATRA and aPD-1. The NE re-educates the tumor's guard to assist T cells in enhanced immunotherapy, broadening the application of aPD-1 in the treatment of anti-PD-1-resistant tumors. Traditional methods of depleting tumor-associated myeloid cells via chemotherapy can easily lead to the re-recruitment of them, eventually resulting in chemo-resistance and presenting obstacles in immunotherapy.