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.

doi:10.1101/2022.08.19.503502

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bioRxiv · 10.1101/2022.08.19.503502

Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment

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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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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.. 2022-08-19. Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment. https://doi.org/10.1101/2022.08.19.503502

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