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An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses.

ABSTRACT: 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 CD34+ stem cells (CD34+ HSC), and combined it with lung cancer cell line-derived human xenografts or patient-derived xenografts (Hu-PDX). Fresh CD34+ HSCs could reconstitute detectable mature human leukocytes (hCD45+) 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 CD34+ 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 CD34+ HSCs. Ex vivo, reconstituted T cells, obtained from the tumor-bearing humanized mice, secreted IFN? 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 CD34+HSCs 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.

SUBMITTER: Meraz IM

PROVIDER: S-EPMC7213862 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses.

Meraz Ismail M IM Majidi Mourad M Meng Feng F Shao RuPing R Ha Min Jin MJ Neri Shinya S Fang Bingliang B Lin Steven H SH Tinkey Peggy T PT Shpall Elizabeth J EJ Morris Jeffrey J Roth Jack A JA

Cancer immunology research 20190611 8

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 CD34+ stem cells (CD34+ HSC), and combined it with lung cancer cell line-derived human xenografts or patient-derived xenografts (Hu-PDX). Fresh CD34+ HSCs could reconstitute detectable mature human leukocytes (hCD45+) in mice at four weeks without the onset of graft-versus-host d ...[more]

PMID: 31186248

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Project description:Breast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models.To circumvent some of the limitations posed by the lack of appropriate animal models in preclinical studies of immunotherapies, partially human leukocyte antigen-matched TNBC PDX tumor lines from our collection, as well as human melanoma cell lines, were engrafted in humanized nonobese diabetic/severe combined immunodeficiency IL2R?null (hNSG) mice obtained by intravenous injection of CD34+ hematopoietic stem cells into nonlethally irradiated 3-4-week-old mice. After both PDXs and melanoma cell xenografts reached ~?150-200 mm3, animals were treated with humanized anti-PD-1 antibody or anti-CTLA-4 and evaluated for tumor growth, survival, and potential mechanism of action.Human CD45+, CD20+, CD3+, CD8+, CD56+, CD68+, and CD33+ cells were readily identified in blood, spleen, and bone marrow collected from hNSG, as well as human cytokines in blood and engrafted tumors. Engraftment of TNBC PDXs in hNSG was high (~?85%), although they grew at a slightly slower pace and conserved their ability to generate lung metastasis. Human CD45+ cells were detectable in hNSG-harbored PDXs, and consistent with clinical observations, anti-PD-1 antibody therapy resulted in both a significant reduction in tumor growth and increased survival in some of the hNSG PDX tumor lines, whereas no such effects were observed in the corresponding non-hNSG models.This study provides evidence associated with anti-PD-1 immunotherapy against TNBC tumors supporting the use of TNBC PDXs in humanized mice as a model to overcome some of the technical difficulties associated with the preclinical investigation of immune-based therapies.

Project description:Gemcitabine (Gem), a nucleoside analog, is a preferred choice of treatment for pancreatic cancer (PCa) and often used in combination therapy against wide range of solid tumors. It is known to be rapidly inactivated in blood by cytidine deaminase. The objective of the study was to improve the systemic stability and anticancer activity of modified Gem termed 4-N-stearoylGem (4NSG) In this study, the IC50 values of 4NSG treated MiaPaCa-2 and primary pancreatic cancer (PPCL-46) cultures were significantly lower when compared with gemcitabine hydrochloride (GemHCl) treated cultures. In acute toxicity study, liver enzyme level of aspartate aminotransferase (AST) of the control mice was not significantly different from AST levels of 4NSG and GemHCl treated mice. However, alanine aminotransferase (ALT) level of control mice (67 ± 5 mUnits/mL) was significantly lower compared with ALT levels of GemHCl (232 ± 28 mUnits/mL) and that of 4NSG (172 ± 22 mUnits/mL) (p < 0.0001). More importantly, ALT level of 4NSG was lower than ALT level of GemHCl (p < 0.05). Although ALT levels were elevated, pathological images of liver and kidney tissues of control, GemHCl and 4NSG treated mice revealed no architectural changes and no significant change in mice weight was observed during treatment. The bioavailability (AUC) of 4NSG was 3-fold high and significantly inhibited the tumor growth as compared with equivalent dose of GemHCl. Immunohistochemical staining revealed that 4NSG significantly inhibited the expression vascular endothelial growth factor (VEGF) receptor. The study is unique because it established, for the first time, enhanced anticancer activity of 4NSG against pancreatic patient-derived xenograft (PDX) mouse model and PPCL-46 cells compared with Gem. 4SGN enhanced pharmacokinetic profile and improved the therapeutic efficacy of the standard-of-care Gem. Lastly, 4GSN showed a remarkable tumor growth inhibition and revealed significant antiangiogenic activity in 4GSN treated pancreatic PDX tumor.

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Dataset Information

An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses.

Publications

An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses.

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