Kyoung Ho Pyo1, Jae Hwan Kim2, Ji-Min Lee3, Sung Eun Kim2, Jae Seok Cho2, Sun Min Lim4, Byoung Chul Cho5. 1. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. 2. Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. 3. Brain Korea 21 PLUS Project for Medical Science, Yonsei University, South Korea. 4. Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, South Korea. Electronic address: smlim@cha.ac.kr. 5. Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. Electronic address: cbc1971@yuhs.ac.
Abstract
BACKGROUND: With the advance of immunotherapy, treatment of non-small-cell lung cancer (NSCLC) has revolutionized by having anti-PD-1 therapy in front-line setting. In this era of cancer immunotherapy, humanized mouse models which recapitulate human immune system, are needed for predicting immunotherapy response in patients. We established a Hu-PBL-NSG mouse model which can be used as a preclinical testing platform for assessing efficacy of different immunotherapeutic agents. MATERIALS AND METHODS: Hu-PBL-NSG mouse model was established by engrafting human peripheral blood mononuclear cells (PBMCs) into NOD/scid/IL-2Rγ-/- (NSG) mice. Cytokine array was performed to assess serological similarity between patient and the Hu-PBL-NSG mouse, and microscopic immune cell infiltration was observed in various organs mouse model. Human anti-PD-1 therapy was treated for assessing drug efficacy in patient-derived tumor. RESULTS: hCD3+hCD45+ T-cells and antigen presenting cells (dendritic cells, macrophages, and MDSC) increased in the serum of Hu-PBL-NSG mouse 24 h after the transfusion of human PBMCs, and CD3 + T cells were observed in lung, liver, kidney, spleen sections. Cytokine arrays of human and Hu-PBL-NSG mouse revealed high similarity of Th1, Th2, Th17-related cytokines. A tumor xenograft was engrafted from an EML4-ALK patient, and Hu-PBL-NSG mouse was sacrificed for histological analyses. hCD3+ T cells were infiltrated within the tumor, and CD11c + cells, which represent antigen-presenting capability, were seen in spleen, lung, liver and kidney. When anti-PD-1 Ab was treated intraperitoneally, xenograft tumor showed significant reduction in volume after day 6, and increased expression of immune response-related genes on microarray analysis in the tumor. Mostly IFN-gamma and its related gene sets were significantly changed (FDR < 0.25, GSEA). CONCLUSION: Hu-PBL-NSG mouse model which highly resembles human immune system was successfully established. This model could be a strong preclinical model for testing efficacy of immunotherapeutic agents, and also for pursuing novel immunotherapy treatment strategies in advanced NSCLC.
BACKGROUND: With the advance of immunotherapy, treatment of non-small-cell lung cancer (NSCLC) has revolutionized by having anti-PD-1 therapy in front-line setting. In this era of cancer immunotherapy, humanized mouse models which recapitulate human immune system, are needed for predicting immunotherapy response in patients. We established a Hu-PBL-NSG mouse model which can be used as a preclinical testing platform for assessing efficacy of different immunotherapeutic agents. MATERIALS AND METHODS: Hu-PBL-NSG mouse model was established by engrafting human peripheral blood mononuclear cells (PBMCs) into NOD/scid/IL-2Rγ-/- (NSG) mice. Cytokine array was performed to assess serological similarity between patient and the Hu-PBL-NSG mouse, and microscopic immune cell infiltration was observed in various organs mouse model. Human anti-PD-1 therapy was treated for assessing drug efficacy in patient-derived tumor. RESULTS: hCD3+hCD45+ T-cells and antigen presenting cells (dendritic cells, macrophages, and MDSC) increased in the serum of Hu-PBL-NSG mouse 24 h after the transfusion of human PBMCs, and CD3 + T cells were observed in lung, liver, kidney, spleen sections. Cytokine arrays of human and Hu-PBL-NSG mouse revealed high similarity of Th1, Th2, Th17-related cytokines. A tumor xenograft was engrafted from an EML4-ALKpatient, and Hu-PBL-NSG mouse was sacrificed for histological analyses. hCD3+ T cells were infiltrated within the tumor, and CD11c + cells, which represent antigen-presenting capability, were seen in spleen, lung, liver and kidney. When anti-PD-1 Ab was treated intraperitoneally, xenograft tumor showed significant reduction in volume after day 6, and increased expression of immune response-related genes on microarray analysis in the tumor. Mostly IFN-gamma and its related gene sets were significantly changed (FDR < 0.25, GSEA). CONCLUSION: Hu-PBL-NSG mouse model which highly resembles human immune system was successfully established. This model could be a strong preclinical model for testing efficacy of immunotherapeutic agents, and also for pursuing novel immunotherapy treatment strategies in advanced NSCLC.
Authors: Lei Huang; Ruiqin Wang; Kun Xie; Jingming Zhang; Fei Tao; Chenyu Pi; Yan Feng; Hua Gu; Jianmin Fang Journal: Breast Cancer Res Treat Date: 2021-10-16 Impact factor: 4.872
Authors: Francis Man; Alexander Koers; Panagiotis Karagiannis; Debra H Josephs; Heather J Bax; Amy E Gilbert; Tihomir S Dodev; Silvia Mele; Giulia Chiarruttini; Silvia Crescioli; Jitesh Chauhan; Julia E Blower; Margaret S Cooper; James Spicer; Sophia N Karagiannis; Philip J Blower Journal: Oncoimmunology Date: 2021-09-06 Impact factor: 8.110