scholarly journals APOBEC3B expression generates an immunogenic model of Kras mutant lung cancer

2020 ◽  
Author(s):  
Sophie de Carné Trécesson ◽  
Jesse Boumelha ◽  
Emily K. Law ◽  
Pablo Romero-Clavijo ◽  
Edurne Mugarza ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Mouse Models ◽  
Cytosine Deaminase ◽  
Adaptive Immune System ◽  
Genetically Engineered ◽  
Human Lung Cancer ◽  
Tumour Regression ◽  
Host Immune System ◽  
Mutational Burden

ABSTRACTMutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant Kras-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This causes an increase in mutational burden in Kras mutant and p53 deleted (KP) tumours and in carcinogen-induced tumours, but these mutations are sub-clonal and do not lead to sensitivity of the autochthonous tumours to immune interventions. However, when clonal cell lines are derived from these tumours they provide an immunogenic syngeneic transplantation lung cancer model that is sensitive to immunotherapy. The ability of a KRAS-G12C inhibitor to cause regression of these tumours is markedly potentiated by the adaptive immune system, providing an opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

scholarly journals Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research

ILAR Journal ◽  
2018 ◽  
Vol 59 (3) ◽  
pp. 247-262 ◽  
Author(s):  
Nana H Overgaard ◽  
Timothy M Fan ◽  
Kyle M Schachtschneider ◽  
Daniel R Principe ◽  
Lawrence B Schook ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cell ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Model Systems ◽  
High Rate ◽  
Host Immune System ◽  
Cancer Immunoediting ◽  
Oncology Research ◽  
Experimental Cancer

Abstract The immune system plays dual roles in response to cancer. The host immune system protects against tumor formation via immunosurveillance; however, recognition of the tumor by immune cells also induces sculpting mechanisms leading to a Darwinian selection of tumor cell variants with reduced immunogenicity. Cancer immunoediting is the concept used to describe the complex interplay between tumor cells and the immune system. This concept, commonly referred to as the three E’s, is encompassed by 3 distinct phases of elimination, equilibrium, and escape. Despite impressive results in the clinic, cancer immunotherapy still has room for improvement as many patients remain unresponsive to therapy. Moreover, many of the preclinical results obtained in the widely used mouse models of cancer are lost in translation to human patients. To improve the success rate of immuno-oncology research and preclinical testing of immune-based anticancer therapies, using alternative animal models more closely related to humans is a promising approach. Here, we describe 2 of the major alternative model systems: canine (spontaneous) and porcine (experimental) cancer models. Although dogs display a high rate of spontaneous tumor formation, an increased number of genetically modified porcine models exist. We suggest that the optimal immuno-oncology model may depend on the stage of cancer immunoediting in question. In particular, the spontaneous canine tumor models provide a unique platform for evaluating therapies aimed at the escape phase of cancer, while genetically engineered swine allow for elucidation of tumor-immune cell interactions especially during the phases of elimination and equilibrium.

scholarly journals The Oncogenic Potential of a Mutant TP53 Gene Explored in Two Spontaneous Lung Cancer Mice Models

2020 ◽  
Author(s):  
Julian Ramelow ◽  
Christopher Brooks ◽  
Li GaO ◽  
Abeer A Almiman ◽  
Terence M Williams ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Lung Tumor ◽  
Mutant Gene ◽  
Genetic Mutation ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Oncogenic Potential ◽  
Age Related

Abstract BackgroundLung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers.MethodsPreviously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.ResultsWe found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.ConclusionsOncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

scholarly journals Immunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help?

2019 ◽  
Vol 2019 ◽  
pp. 1-18
Author(s):  
Rachel E. Cooke ◽  
Rachel Koldej ◽  
David Ritchie
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Mouse Models ◽  
3D Culture ◽  
Adaptive Immune System ◽  
Course Of Disease ◽  
Susceptibility To Infection ◽  
Age Related ◽  
Immune Defects ◽  
Immune Profiling

Multiple myeloma (MM) is usually diagnosed in older adults at the time of immunosenescence, a collection of age-related changes in the immune system that contribute to increased susceptibility to infection and cancer. The MM tumor microenvironment and cumulative chemotherapies also add to defects in immunity over the course of disease. In this review we discuss how mouse models have furthered our understanding of the immune defects caused by MM and enabled immunotherapeutics to progress to clinical trials, but also question the validity of using immunodeficient models for these purposes. Immunocompetent models, in particular the 5T series and Vk⁎MYC models, are increasingly being utilized in preclinical studies and are adding to our knowledge of not only the adaptive immune system but also how the innate system might be enhanced in anti-MM activity. Finally we discuss the concept of immune profiling to target patients who might benefit the most from immunotherapeutics, and the use of humanized mice and 3D culture systems for personalized medicine.

scholarly journals Progress and applications of mouse models for human lung cancer

2010 ◽  
Vol 35 (2) ◽  
pp. 426-443 ◽  
Author(s):  
S. de Seranno ◽  
R. Meuwissen
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Human Lung Cancer

scholarly journals Preliminary Study of the Effect of Stereotactic Body Radiotherapy (SBRT) on the Immune System in Lung Cancer Patients Unfit for Surgery: Immunophenotyping Analysis

2018 ◽  
Vol 19 (12) ◽  
pp. 3963 ◽  
Author(s):  
Arturo Navarro-Martín ◽  
Isabel Galiana ◽  
Miguel Berenguer Frances ◽  
Jon Cacicedo ◽  
Rut Cañas Cortés ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Cancer Patients ◽  
Stereotactic Body Radiotherapy ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Host Immune System ◽  
Lung Cancer Patients ◽  
Specific Increase ◽  
Relevant Finding

An immunophenotyping analysis was performed in peripheral blood samples from seven patients with lung cancer unfit for surgery treated with stereotactic body radiotherapy (SBRT). The objective was to characterize the effect of SBRT on the host immune system. Four patients received 60 Gy (7.5 Gy × 8) and three 50 Gy (12.5 Gy × 4). Analyses were performed before SBRT, 72 h after SBRT, and at one, three, and six months after the end of SBRT. Of note, there was a specific increase of the immunoactive component of the immune system, with elevation of CD56+highCD16+ natural killer (NK) cells (0.95% at baseline to 1.38% at six months), and a decrease of the immunosuppressive component of the immune system, with decreases of CD4+CD25+Foxp3+CDA5RA− regulatory T cells (4.97% at baseline to 4.46% at six months), granulocytic myeloid-derived suppressor cells (G-MDSCs) (from 66.1% at baseline to 62.6% at six months) and monocytic (Mo-MDSCs) (8.2% at baseline to 6.2% at six months). These changes were already apparent at 72 h and persisted over six months. SBRT showed an effect on systemic immune cell populations, which is a relevant finding for supporting future combinations of SBRT with immunotherapy for treating lung cancer patients.

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