Development of a human glioblastoma model using humanized DRAG mice for immunotherapy

Rashmi Srivastava; Alireza Labani-Motlagh; Apeng Chen; Jose Alejandro Bohorquez; Bin Qin; Meghana Dodda; Fan Yang; Danish Ansari; Sahil Patel; Honglong Ji; Scott Trasti; Yapeng Chao; Yash Patel; Han Zou; Baoli Hu; Guohua Yi

doi:10.1093/abt/tbad021

Development of a human glioblastoma model using humanized DRAG mice for immunotherapy

Antib Ther. 2023 Oct 4;6(4):253-264. doi: 10.1093/abt/tbad021. eCollection 2023 Oct.

Authors

Rashmi Srivastava^{1

2}, Alireza Labani-Motlagh^{3

4

5}, Apeng Chen⁶, Jose Alejandro Bohorquez^{3

4

5}, Bin Qin^{1

2

7}, Meghana Dodda^{1

2}, Fan Yang^{3

4

5}, Danish Ansari^{3

4

5}, Sahil Patel^{3

4

5}, Honglong Ji^{4

5}, Scott Trasti⁸, Yapeng Chao^{1

2}, Yash Patel^{1

2}, Han Zou^{1

2}, Baoli Hu^{1

2

9}, Guohua Yi^{3

4

5}

Affiliations

¹ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
² John G. Rangos Sr. Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
³ Department of Medicine, The University of Texas at Tyler School of Medicine, Tyler, TX 75708, USA.
⁴ Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
⁵ Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
⁶ State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China.
⁷ National Centre for International Research in Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, People's Republic of China.
⁸ Laboratory Animal Resource Center, Texas Tech University Health Sciences Center, Lubbock, TX 79410, USA.
⁹ Cancer Biology Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.

Abstract

Glioblastoma (GBM) is the most common and lethal primary brain tumor. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. We successfully generated humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model by transplantation of human DR4⁺ hematopoietic stem cells (hHSCs), and effectively grafted GBM patient-derived tumorsphere cells to form xenografted tumors intracranially. The engrafted tumors recapitulated the pathological features and the immune cell composition of human GBM. Administration of anti-human PD-1 antibodies in these tumor-bearing humanized DRAG mice decreased the major tumor-infiltrating immunosuppressive cell populations, including CD4⁺PD-1⁺ and CD8⁺PD-1⁺ T cells, CD11b⁺CD14⁺HLA-DR⁺ macrophages, CD11b⁺CD14⁺HLA-DR^-CD15^- and CD11b⁺CD14^-CD15⁺ myeloid-derived suppressor cells, indicating the humanized DRAG mice as a useful model to test the efficacy of GBM immunotherapy. Taken together, these results suggest that the humanized DRAG mouse model is a reliable preclinical platform for studying brain cancer immunotherapy and beyond.

Keywords: brain cancer immunotherapy; glioblastomas; humanized DRAG mice; tumor immune microenvironment; tumor-infiltrating immunosuppressive cells.

Abstract

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