1. Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment
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Jan Martinek, Ryan C Fields, Scott Gettinger, Karolina Palucka, Katerina Politi, Jun Zhao, Ye Bi, Richard A Flavell, Frank Detterbeck, Obi Griffith, Liang Shan, Malachi Griffith, Michael Chiorazzi, Bradley Krasnick, Yunjiang Zheng, Keenan J Robbins, Rihao Qu, Gabriel Kaufmann, Zachary Skidmore, Melani Juric, Laura A Henze, Frederic Brösecke, Adam Adonyi, Esen Sefik, Jacqueline Mudd, S Peter Goedegebuure, Abimbola Oyedeji, Sofia Fertuzinhos, Rolando Garcia-Milian, Daniel Boffa, Andrew Dhanasopon, Justin Blasberg, Benjamin Judson, and Yuval Kluger more...
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - 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. more...
- Published
- 2023
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