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Animal models for studying tumor microenvironment (TME) and resistance to lymphocytic infiltration.

ABSTRACT: In cancer immunotherapy, cytotoxic T or NK cells need to engage cancer cells to initiate the killing. However, in clinical studies and in mouse models, some solid tumors are found with no lymphocytes. It is likely that these tumors will be resistant to all sorts of immunotherapies. Thus, restoring lymphocytic infiltration will be vital to the success of immunotherapies on solid tumors. In order to understand the complex interaction between cancer cells and stromal cells, we propose to establish animal models for studying the tumor microenvironment and to develop and test therapies to restore lymphocytic infiltration of tumors Without lymphocytes infiltrating tumors, all immunotherapies on solid tumors become ineffective.

SUBMITTER: Yamaguchi R

PROVIDER: S-EPMC6154837 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Animal models for studying tumor microenvironment (TME) and resistance to lymphocytic infiltration.

Yamaguchi Ryuji R Perkins Guy G

Cancer biology & therapy 20180516 9

In cancer immunotherapy, cytotoxic T or NK cells need to engage cancer cells to initiate the killing. However, in clinical studies and in mouse models, some solid tumors are found with no lymphocytes. It is likely that these tumors will be resistant to all sorts of immunotherapies. Thus, restoring lymphocytic infiltration will be vital to the success of immunotherapies on solid tumors. In order to understand the complex interaction between cancer cells and stromal cells, we propose to establish ...[more]

PMID: 29723108

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Project description:One of the most intriguing issues in the hepatitis E virus (HEV) field is the significant increase in mortality rates of the mother and fetus when infection occurs in the second and third trimesters of gestation. A virus that is normally self-limiting and has a mortality rate of less than one percent in otherwise healthy individuals steeply rises by up to 30% in these pregnant populations. Answering this pivotal question has not been a simple task. HEV, in general, has been a difficult pathogen to understand in the laboratory setting. A historical lack of ability to efficiently propagate the virus in tissue culture models has led to many molecular aspects of the viral lifecycle being understudied. Although great strides have been made in recent years to adapt viruses to cell culture, this field remains behind other viruses that are much easier to replicate efficiently in vitro. Some of the greatest discoveries regarding HEV have come from using animal models for which naturally occurring strains of HEV have been identified, including pigs and chickens, but key limitations have made animal models imperfect for studying all aspects of human HEV infections. In addition to the difficulties working with HEV, pregnancy is a very complicated biological process with an elaborate interplay between many different host systems, including hormones, cardiovascular, kidneys, respiratory, gastrointestinal, epithelial, liver, metabolic, immune, and others. Significant differences between the timing and interplay of these systems are notable between species, and making direct comparisons between animals and humans can be difficult at times. No simple answer exists as to how HEV enhances mortality in pregnant populations. One of the best approaches to studying HEV in pregnancy is likely a combinatorial approach that uses the best combination of emerging in vitro and in vivo systems while accounting for the deficiencies that are present in each model. This review describes many of the current HEV animal model systems and the strengths and weaknesses of each as they apply to HEV pregnancy-associated mortality. We consider factors that are critical to analyzing HEV infection within the host and how, despite no perfect animal model for human pregnancy mortality existing, recent developments in HEV models, both in vitro and in vivo, are advancing our overall understanding of HEV in the pregnant host.

Project description:BackgroundEpigenetic regulation and immunotherapy of tumor microenvironment (TME) is a hot topic in recent years. However, the potential value of tryptophan metabolism genes in regulating TME and immunotherapy is still unclear.Materials and methodsA comprehensive study of glioma patients was carried out based on 40 tryptophan metabolic genes. Subsequently, these prognostic tryptophan metabolic genes are systematically associated with immunological characteristics and immunotherapy. A risk score model was constructed and verified in the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) cohorts to provide guidance for prognosis prediction and immunotherapy of glioma patients.ResultsWe described the changes of tryptophan metabolism genes in 966 glioma samples from genetic and transcriptional fields and evaluated their expression patterns from two independent data sets. We identified two different molecular subtypes and found that two subtypes were associated with clinicopathological features, prognosis, TME cell infiltration, and immune checkpoint blockers (ICBs). Then, four genes (IL4I1, CYP1A1, OGDHL, and ASMT) were screened out by univariate and multivariate cox regression analysis of tryptophan metabolism genes, and a risk score model for predicting the overall survival (OS) of glioma patients was constructed. And its predictive ability is verified using the CGGA database. At the same time, we verified the expression of IL4I1, CYP1A1, OGDHL, and ASMT four genes in glioma specimens and cell lines in GES4260 and GES15824. Therefore, we constructed a nomogram to improve the clinical applicability of the risk assessment model. The high risk score group, characterized by increased TMB and immune cell infiltration, was also sensitive to temozolomide immunotherapy. Our comprehensive analysis of tryptophan metabolic genes in gliomas shows that they play a potential role in tumor immune stromal microenvironment, clinicopathological features, and prognosis.ConclusionTryptophan metabolism genes play an indispensable role in the complexity, diversity, and prognosis of TME. This risk score model based on tryptophan metabolism gene is a new predictor of clinical prognosis and immunotherapy response of glioma, and guides a more appropriate immunotherapy strategy for glioma patients.

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Dataset Information

Animal models for studying tumor microenvironment (TME) and resistance to lymphocytic infiltration.

Publications

Animal models for studying tumor microenvironment (TME) and resistance to lymphocytic infiltration.

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