Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment
Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment
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 patient's 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.
Krasnick Bradley、Robbins Keenan J、Brosecke Frederic、Sefik Esen、Bi Ye、Goedegebuure S Peter、Griffith Obi、Garcia-Milian Rolando、Gettinger Scott、Detterbeck Frank、Skidmore Zachary、Zhao Jun、Chiorazzi Michael、Martinek Jan、Zheng Yunjiang、Fields Ryan、Oyedeji Abimbola、Flavell Richard A、Henze Laura A、Dhanasopon Andrew、Kaufmann Gabriel、Mudd Jacqueline、Griffith Malachi、Boffa Daniel、Adonyi Adam、Politi Katerina、Blasberg Justin、Shan Liang、Palucka A Karolina、Kluger Yuval、Qu Rihao、Fertuzinhos Sofia、Judson Benjamin
医学研究方法肿瘤学基础医学
Krasnick Bradley,Robbins Keenan J,Brosecke Frederic,Sefik Esen,Bi Ye,Goedegebuure S Peter,Griffith Obi,Garcia-Milian Rolando,Gettinger Scott,Detterbeck Frank,Skidmore Zachary,Zhao Jun,Chiorazzi Michael,Martinek Jan,Zheng Yunjiang,Fields Ryan,Oyedeji Abimbola,Flavell Richard A,Henze Laura A,Dhanasopon Andrew,Kaufmann Gabriel,Mudd Jacqueline,Griffith Malachi,Boffa Daniel,Adonyi Adam,Politi Katerina,Blasberg Justin,Shan Liang,Palucka A Karolina,Kluger Yuval,Qu Rihao,Fertuzinhos Sofia,Judson Benjamin.Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment[EB/OL].(2025-03-28)[2025-08-03].https://www.biorxiv.org/content/10.1101/2022.08.19.503502.点此复制
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