Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment. J Immunother Cancer. 2023;11(7).
JGM, Humans, Animals, Mice, Vascular Endothelial Growth Factor A, Tumor Microenvironment, Neoplasms, Medical Oncology, Disease Models, Animal
J Immunother Cancer. 2023;11(7).
This work was funded by the Howard Hughes Medical Institute (RAF), National Institute of Health grant T32HL007974 (MC), National Institute of Health grant K08CA245211 (MC), Yale SPORE in Head and Neck Cancer P50DE030707 (MC), Yale SPORE in Lung Cancer P50CA196530 (MC and RAF), NIH Research Grant P30CA016359 from the National Cancer Institute (MC and RAF), National Institute of Health grant R01CA248277 (RCF and RAF), National Institute of Health grant T32CA009621 (KR and BK), National Cancer Institute Cancer Center Support Grant P30CA091842 (RCF), Washington University PDX Development and Trial Center U54CA224083 (RCF) Funding from The Alvin J. Siteman Cancer Center Siteman Investment Program, The Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, the Barnard Trust, David Riebel Cancer Research Fund (RCF). Siteman Tissue Procurement Core and the core grant/services of the Washington University Digestive Diseases Research Core Center (P30 DK052574).
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.