학술논문
Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment
Document Type
article
Author
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; Yuval Kluger
Source
Journal for ImmunoTherapy of Cancer, Vol 11, Iss 7 (2023)
Subject
Language
English
ISSN
2051-1426
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.