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Immune response in lung cancer mouse model mimics human anti-Hu reactivity.

ABSTRACT: Most patients with paraneoplastic encephalomyelitis/sensory neuronopathy PEM/SN have small-cell lung cancer (SCLC) and develop antibodies against neuronal-specific Hu proteins, which are abnormally expressed in the tumor. Anti-Hu reactivity is present in ~16% of SCLC patients without PEM/SN. Here we test the hypothesis that engineered SCLC-prone mice may exhibit anti-Hu reactivity. We show that tumors from SCLC-prone mice misexpress Hu proteins, and 14% of mice harbor anti-Hu antibodies. Mice appear to show reactivity prior to clinical diagnosis of SCLC. This mouse model system will be useful to study SCLC-associated autoimmunity, its diagnostic value, and the potential protective role of oncoantigen-directed autoantibodies.

SUBMITTER: Kazarian M

PROVIDER: S-EPMC2788043 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Immune response in lung cancer mouse model mimics human anti-Hu reactivity.

Kazarian Meleeneh M Calbo Joaquim J Proost Natalie N Carpenter Catherine L CL Berns Anton A Laird-Offringa Ite A IA

Journal of neuroimmunology 20090917 1-2

Most patients with paraneoplastic encephalomyelitis/sensory neuronopathy PEM/SN have small-cell lung cancer (SCLC) and develop antibodies against neuronal-specific Hu proteins, which are abnormally expressed in the tumor. Anti-Hu reactivity is present in ~16% of SCLC patients without PEM/SN. Here we test the hypothesis that engineered SCLC-prone mice may exhibit anti-Hu reactivity. We show that tumors from SCLC-prone mice misexpress Hu proteins, and 14% of mice harbor anti-Hu antibodies. Mice ap ...[more]

PMID: 19765830

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Project description:BackgroundAdaptive immune resistance induces an immunosuppressive tumor environment that enables immune evasion. This phenomenon results in tumor escape with progression and metastasis. Programmed cell death-ligand 1 (PD-L1) expressed on tumors is thought to inhibit tumor-infiltrating lymphocytes (TILs) through programmed cell death 1 (PD1), enabling adaptive immune resistance. This study investigates the role of PD-L1 in both mouse and human neuroblastoma immunity. The consequence of PD-L1 inhibition is characterized in the context of an established whole tumor cell vaccine.Methods and findingsA mouse model of neuroblastoma was investigated using an Id2 knockdown whole cell vaccine in combination with checkpoint inhibition. We show that immunogenic mouse neuroblastoma acquires adaptive immune resistance by up-regulating PD-L1 expression, whereas PD-L1 is of lesser consequence in nonimmunogenic neuroblastoma tumors. Combining PD-L1 checkpoint inhibition with whole tumor cell/anti-CTLA-4 vaccination enhanced tumor cell killing, cured mice with established tumors, and induced long-term immune memory (6 months). From an evaluation of patient neuroblastoma tumors, we found that the inflammatory environment of the mouse neuroblastoma mimicked human disease in which PD-L1 expression was associated directly with TILs and lower-risk tumors. High-risk patient tumors were lacking both TILs and PD-L1 expression. Although a correlation in immunity seems to exist between the mouse model and human findings, the mouse tumor model is induced and not spontaneously occurring, and furthermore, the number of both mouse and human correlates is limited.ConclusionsThis study demonstrates the role PD-L1 plays in neuroblastoma's resistance to immunity and defines the nonredundant effect of combination checkpoint inhibition with vaccine therapy in a mouse model. High-risk, nonimmunogenic human tumors display both diminished PD-L1 expression and adaptive immune resistance. Paradoxically, high-risk tumors may be more responsive to effective vaccine therapy because of their apparent lack of adaptive immune resistance.

Project description:Owing to its ability to form biofilms, Staphylococcus aureus is responsible for an increasing number of infections on implantable medical devices. The aim of this study was to develop a mouse model using microbeads coated with S. aureus biofilm to simulate such infections and to analyse the dynamics of anti-biofilm inflammatory responses by intravital imaging. Scanning electron microscopy and flow cytometry were used in vitro to study the ability of an mCherry fluorescent strain of S. aureus to coat silica microbeads. Biofilm-coated microbeads were then inoculated intradermally into the ear tissue of LysM-EGFP transgenic mice (EGFP fluorescent immune cells). General and specific real-time inflammatory responses were studied in ear tissue by confocal microscopy at early (4-6h) and late time points (after 24h) after injection. The displacement properties of immune cells were analysed. The responses were compared with those obtained in control mice injected with only microbeads. In vitro, our protocol was capable of generating reproducible inocula of biofilm-coated microbeads verified by labelling matrix components, observing biofilm ultrastructure and confirmed in vivo and in situ with a matrix specific fluorescent probe. In vivo, a major inflammatory response was observed in the mouse ear pinna at both time points. Real-time observations of cell recruitment at injection sites showed that immune cells had difficulty in accessing biofilm bacteria and highlighted areas of direct interaction. The average speed of cells was lower in infected mice compared to control mice and in tissue areas where direct contact between immune cells and bacteria was observed, the average cell velocity and linearity were decreased in comparison to cells in areas where no bacteria were visible. This model provides an innovative way to analyse specific immune responses against biofilm infections on medical devices. It paves the way for live evaluation of the effectiveness of immunomodulatory therapies combined with antibiotics.

Dataset Information

Immune response in lung cancer mouse model mimics human anti-Hu reactivity.

Publications

Immune response in lung cancer mouse model mimics human anti-Hu reactivity.

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