Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment
Michael Chiorazzi, Jan Martínek, Bradley A. Krasnick, Yunjiang Zheng, Keenan J. Robbins, Rihao Qu, Gabriel Kaufmann, Zachary Skidmore, Melani Juric, Laura A Henze, Frederic Brösecke, Adam Adonyi, Jun Zhao, Liang Shan, Esen Sefik, Jacqueline L. Mudd, Ye Bi, S. Peter Goedegebuure, Malachi Griffith, Obi L. Griffith, Abimbola Oyedeji, Sofia Fertuzinhos, Rolando García-Milian, Daniel J. Boffa, Frank C. Detterbeck, Andrew P. Dhanasopon, Justin D. Blasberg, Benjamin L. Judson, Scott Gettinger, Katerina Politi, Yuval Kluger, Karolina Palucka, Ryan C. Fields, Richard A. Flavell
Abstract
BACKGROUND: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. RESULTS: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. CONCLUSIONS: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing.