Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment
Chiorazzi, M.; Martinek, J.; Krasnick, B.; Zheng, Y.; Robbins, K. J.; Qu, R.; Kaufmann, G.; Skidmore, Z.; Henze, L. A.; Brosecke, F.; Adonyi, A.; Zhao, J.; Shan, L.; Sefik, E.; Mudd, J.; Bi, Y.; Goedegebuure, S. P.; Griffith, M.; Griffith, O.; Oyedeji, A.; Fertuzinhos, S.; Garcia-Milian, R.; Boffa, D.; Detterbeck, F.; Dhanasopon, A.; Blasberg, J.; Judson, B.; Gettinger, S.; Politi, K.; Kluger, Y.; Palucka, A. K.; Fields, R.; Flavell, R. A.
Show abstract
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 inter-species differences between human and mouse, as well as inter-person germline and somatic variation. Here we develop an autologous system that models the TME in individual patients. With patient-derived bone marrow, we engrafted a patients hematopoietic system in MISTRG6 mice followed by patient-derived xenograft (PDX) tissue, providing a genetically matched autologous model. We used this system to prospectively study tumor-immune interactions in solid tumor patients. 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 VEGF-A signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth, demonstrating the utility of the autologous PDX system for pre-clinical testing.
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