TY - JOUR
T1 - An improved patient-derived xenograft humanized mouse model for evaluation of lung cancer immune responses
AU - Meraz, Ismail M.
AU - Majidi, Mourad
AU - Meng, Feng
AU - Shao, Ru Ping
AU - Ha, Min Jin
AU - Neri, Shinya
AU - Fang, Bingliang
AU - Lin, Steven H.
AU - Tinkey, Peggy T.
AU - Shpall, Elizabeth J.
AU - Morris, Jeffrey
AU - Roth, Jack A.
N1 - Funding Information:
J.A. Roth reports receiving a commercial research grant from The University of Texas MD Anderson Cancer Center, sponsored research agreement from Gen-prex, Inc, has ownership interest (including stock, patents, etc.) in Genprex, Inc., and is a consultant/advisory board member for Genprex, Inc. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We acknowledge MDACC Flow cytometry and imaging core laboratory; MD Anderson animal facility for providing dedicated housing room for humanized mice; MD Anderson Cord Blood Core for providing fresh human cord blood units; MD Anderson HLA-typing core; Ran Zhang, Li Wang and Xiaoshan Zhang from MD Anderson PDX core for providing PDXs; MD Anderson Department of Scientific Publication and Dara S. Keener for her assistance with manuscript formatting and submission. This work was supported in part by the NIH/NCI through The University of Texas MD Anderson Cancer Center's Cancer Center Support Grant (CCSG) CA-016672—Lung Program and Shared Core Facilities (to J.A. Roth); Specialized Program of Research Excellence (SPORE) Grant CA-070907 (to J.A. Roth); PDX Development and Trial Grant U54CA-224065 (to J.A. Roth); Lung Cancer Moon Shot Program (to J.A. Roth), The University of Texas MD Anderson Cancer Center, sponsored research agreement from Genprex, Inc; and Petrin Foundation.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Human tumor xenograft models do not replicate the human immune system and tumor microenvironment. We developed an improved humanized mouse model, derived from fresh cord blood CD34þ stem cells (CD34þ HSC), and combined it with lung cancer cell line–derived human xenografts or patient-derived xenografts (Hu-PDX). Fresh CD34þ HSCs could reconstitute detectable mature human leukocytes (hCD45þ) in mice at four weeks without the onset of graft-versus-host disease (GVHD). Repopulated human T cells, B cells, natural killer (NK) cells, dendritic cells (DC), and myeloid-derived suppressor cells (MDSC) increased in peripheral blood, spleen, and bone marrow over time. Although cultured CD34þ HSCs labeled with luciferase could be detected in mice, the cultured HSCs did not develop into mature human immune cells by four weeks, unlike fresh CD34þ HSCs. Ex vivo, reconstituted T cells, obtained from the tumor-bearing humanized mice, secreted IFNg upon treatment with phorbol myristate acetate (PMA) or exposure to human A549 lung tumor cells and mediated antigen-specific CTL responses, indicating functional activity. Growth of engrafted PDXs and tumor xenografts was not dependent on the human leukocyte antigen status of the donor. Treatment with the anti–PD-1 checkpoint inhibitors pembrolizumab or nivolumab inhibited tumor growth in humanized mice significantly, and correlated with an increased number of CTLs and decreased MDSCs, regardless of the donor HLA type. In conclusion, fresh CD34þHSCs are more effective than their expanded counterparts in humanizing mice, and do so in a shorter time. The Hu-PDX model provides an improved platform for evaluation of immunotherapy.
AB - Human tumor xenograft models do not replicate the human immune system and tumor microenvironment. We developed an improved humanized mouse model, derived from fresh cord blood CD34þ stem cells (CD34þ HSC), and combined it with lung cancer cell line–derived human xenografts or patient-derived xenografts (Hu-PDX). Fresh CD34þ HSCs could reconstitute detectable mature human leukocytes (hCD45þ) in mice at four weeks without the onset of graft-versus-host disease (GVHD). Repopulated human T cells, B cells, natural killer (NK) cells, dendritic cells (DC), and myeloid-derived suppressor cells (MDSC) increased in peripheral blood, spleen, and bone marrow over time. Although cultured CD34þ HSCs labeled with luciferase could be detected in mice, the cultured HSCs did not develop into mature human immune cells by four weeks, unlike fresh CD34þ HSCs. Ex vivo, reconstituted T cells, obtained from the tumor-bearing humanized mice, secreted IFNg upon treatment with phorbol myristate acetate (PMA) or exposure to human A549 lung tumor cells and mediated antigen-specific CTL responses, indicating functional activity. Growth of engrafted PDXs and tumor xenografts was not dependent on the human leukocyte antigen status of the donor. Treatment with the anti–PD-1 checkpoint inhibitors pembrolizumab or nivolumab inhibited tumor growth in humanized mice significantly, and correlated with an increased number of CTLs and decreased MDSCs, regardless of the donor HLA type. In conclusion, fresh CD34þHSCs are more effective than their expanded counterparts in humanizing mice, and do so in a shorter time. The Hu-PDX model provides an improved platform for evaluation of immunotherapy.
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U2 - 10.1158/2326-6066.CIR-18-0874
DO - 10.1158/2326-6066.CIR-18-0874
M3 - Article
C2 - 31186248
AN - SCOPUS:85070498386
SN - 2326-6066
VL - 7
SP - 1267
EP - 1279
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 8
ER -