Patient-derived non-small cell lung cancer xenograft mirrors complex tumor heterogeneity

Chen, Xuanming; Shen, Cheng; Wei, Zhe; Zhang, Rui; Wang, Yongsheng; Chen, Ke; Qiu, Shuang; Zhang, Yuanli; Zhang, Ting; Chen, Bin; Xu, Yanjun; Feng, Qiyi; Huang, Jen‐Wei; Zhong, Zhihui; Che, Guowei; Xiao, Kai

doi:10.20892/j.issn.2095-3941.2020.0012

Cited by 25 publications

(16 citation statements)

References 41 publications

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“…To address these challenges, we performed SNP genotyping of primary tumor samples and their derivative PDXs to evaluate the genomic fidelity and stability of those models. The PDX lines investigated here largely retain the genomic features of primary tumors, as has been shown by others [8,10,11,61,62]; however, we observed some degree of genomic variation and instability. The genomic drift was most noticeable during PDX initiation, showing the highest SNP alteration rate (4.7%) between the patient's tumor (PT) and the first PDX passage (P1).…”

Section: Discussionsupporting

confidence: 80%

Patient-Derived Xenografts of High-Grade Serous Ovarian Cancer Subtype as a Powerful Tool in Pre-Clinical Research

Cybula

Wang

et al. 2021

Cancers

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(1) Background. PDX models have become the preferred tool in research laboratories seeking to improve development and pre-clinical testing of new drugs. PDXs have been shown to capture the cellular and molecular characteristics of human tumors better than simpler cell line-based models. More recently, however, hints that PDXs may change their characteristics over time have begun to emerge, emphasizing the need for comprehensive analysis of PDX evolution. (2) Methods. We established a panel of high-grade serous ovarian carcinoma (HGSOC) PDXs and developed and validated a 300-SNP signature that can be successfully utilized to assess genetic drift across PDX passages and detect PDX contamination with lymphoproliferative tissues. In addition, we performed a detailed histological characterization and functional assessment of multiple PDX passages. (3) Results. Our data show that the PDXs remain largely stable throughout propagation, with marginal genetic drift at the time of PDX initiation and adaptation to mouse host. Importantly, our PDX lines retained the major histological characteristics of the original patients’ tumors even after multiple passages in mice, demonstrating a strong concordance with the clinical responses of their corresponding patients. (4) Conclusions. Our data underline the value of defined HGSOC PDXs as a pre-clinical tumor model.

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Section: Discussionsupporting

confidence: 80%

Patient-Derived Xenografts of High-Grade Serous Ovarian Cancer Subtype as a Powerful Tool in Pre-Clinical Research

Cybula

Wang

et al. 2021

Cancers

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“…To generate humanized mice, we used immuno-compromised NOD.SCID.γc-null (NSG) mice, which are deprived of murine T, B, and NK cells, but that retain functionally immature macrophages and granulocytes [ 29 ]. Patient-derived xenografts (PDX) have been shown to faithfully recapitulate tumor architecture and clinical features in breast [ 30 ], ovarian [ 31 ], lung [ 32 ], skin [ 33 ], and prostate [ 34 ] cancers. However, it is challenging to generate PDX mouse models on a regular and consistent basis.…”

Section: Introductionmentioning

confidence: 99%

Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice

Aubert

Brunel

Olive

et al. 2021

Cancers

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The herpes virus entry mediator (HVEM) delivers a negative signal to T cells mainly through the B and T lymphocyte attenuator (BTLA) molecule. Thus, HVEM/BTLA may represent a novel immune checkpoint during an anti-tumor immune response. However, a formal demonstration that HVEM can represent a target for cancer immunotherapy is still lacking. Here, we first showed that HVEM and BTLA mRNA expression levels were associated with a worse progression-free interval in patients with prostate adenocarcinomas, indicating a detrimental role for the HVEM/BTLA immune checkpoint during prostate cancer progression. We then showed that administration of a monoclonal antibody to human HVEM resulted in a twofold reduction in the growth of a prostate cancer cell line in NOD.SCID.gc-null mice reconstituted with human T cells. Using CRISPR/Cas9, we showed that the therapeutic effect of the mAb depended on HVEM expression by the tumor, with no effect on graft vs. host disease or activation of human T cells in the spleen. In contrast, the proliferation and number of tumor-infiltrating leukocytes increased following treatment, and depletion of CD8+ T cells partly alleviated treatment’s efficacy. The expression of genes belonging to various T cell activation pathways was enriched in tumor-infiltrating leukocytes, whereas genes associated with immuno-suppressive pathways were decreased, possibly resulting in modifications of leukocyte adhesion and motility. Finally, we developed a simple in vivo assay in humanized mice to directly demonstrate that HVEM expressed by the tumor is an immune checkpoint for T cell-mediated tumor control. Our results show that targeting HVEM is a promising strategy for prostate cancer immunotherapy.

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“…To generate humanized mice, we used immuno-compromised NOD.SCID.γc null (NSG) mice, which are deprived of murine T-, B-and NK-cells but that retain functionally immature macrophages and granulocytes [23]. Patient-Derived Xenografts (PDX) have been shown to faithfully recapitulate tumor architecture and clinical features for breast [24] , ovarian [25] , lung [26] , skin [27] and prostate [28] cancers, for instance. However, PDX mice models are difficult to generate on a regular and consistent basis.…”

Section: Introductionmentioning

confidence: 99%

HVEM is a Novel Immune Checkpoint for Prostate Cancer Immunotherapy in Humanized Mice

Aubert¹,

Brunel²,

Olive³

et al. 2021

Preprint

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The Herpes Virus Entry Mediator (HVEM) delivers a negative signal to T cells mainly through the B and T Lymphocyte Attenuator (BTLA) molecule and thus, could represent a novel immune checkpoint during an anti-tumor immune response. A formal demonstration that HVEM can be targeted for cancer immunotherapy is however still lacking. Here, we first show that HVEM and BTLA were associated to a worse prognosis in patients with prostate adenocarcinomas, indicating a detrimental role for this pair of molecule during prostate cancer progression. We then show that a monoclonal antibody to human HVEM significantly impacted the growth of a prostate cancer cell line in immuno-compromised NOD.SCID.gc-null mice reconstituted with human T cells. Using CRISPR/Cas9, we showed that HVEM expression by the tumor was mandatory to observe the therapeutic effect. Mechanistically, tumor control was dependent on CD8+ T cells and was associated to an increase in the proliferation and number of tumor-infiltrating leukocytes. Accordingly, the expression of genes belonging to various T cell activation pathways were enriched in tumor infiltrating leukocytes, whereas genes associated with immuno-suppressive pathways were decreased, possibly resulting in modifications of leukocyte adhesion and motility. Finally, we developed a simple in vivo assay in humanized mice to directly demonstrate that HVEM was an immune checkpoint for T-cell mediated tumor control. Our results show that targeting HVEM is a promising strategy for prostate cancer immunotherapy.

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Patient-derived non-small cell lung cancer xenograft mirrors complex tumor heterogeneity

Cited by 25 publications

References 41 publications

Patient-Derived Xenografts of High-Grade Serous Ovarian Cancer Subtype as a Powerful Tool in Pre-Clinical Research

Patient-Derived Xenografts of High-Grade Serous Ovarian Cancer Subtype as a Powerful Tool in Pre-Clinical Research

Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice

HVEM is a Novel Immune Checkpoint for Prostate Cancer Immunotherapy in Humanized Mice

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