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Choose mouse model for Tumor Immunotherapy Research

2021-10-08
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The direction of tumor immunity is undoubtedly one of the most popular directions in the field of cancer research today, but for researchers who are new to this field, the results of using only the mouse tumor model used in the previous tumor research will not be convincing. For example, The most common human tumor cell line is the tumorigenesis model on immunodeficient mice. The deficiency of the immune system leads to partial or complete loss of the tumor immune microenvironment. It is used to evaluate PD-L1/PD-1 inhibition. The effect of the drug and CAR-T solid tumors is not rigorous enough.

So which tumor models are currently suitable for research in the direction of tumor immunotherapy? This article will do a simple review for everyone.

Syngeneic Tumor Mouse Model

Syngeneic tumor model refers to a model that uses tumor cell lines of the same species to inoculate and form tumors on that species. Common mouse strains can be C57BL/6, BALB/c and FVB, etc. The inoculation method is usually subcutaneous tumor formation or Tail vein tumor formation and in situ tumor formation, this model is characterized by fast tumor formation time, usually only about 4 weeks (see the figure below).

From the perspective of the degree of simulation of the immune microenvironment, the final tumor microenvironment is still different from the native tumor microenvironment, and will be affected by the number of inoculations, the method of inoculation, the site of inoculation, and even the inflammation caused by the injection itself. It will also affect the formation of TME. Relatively speaking, tumor formation in situ usually better mimics the tumor microenvironment, but it also requires more difficulty in operation. One problem with the mouse model of homologous tumors is that the formed tumors are not heterogeneous enough, because they are all derived from the same cell line, the level of tumor heterogeneity will also have an impact on the effect of tumor immunotherapy.

Genetically Engineered Mouse Models

Gene-edited tumor mouse models are usually spontaneous tumor models. Through systemic or tissue-specific overexpression of oncogenes, or knockout of tumor suppressor genes, tumors are formed in mice, such as KRAS, MYC overexpressing breast cancer Mouse models, P53 or PTEN knockout mouse models of prostate cancer, tamoxifen-induced Cre-loxP specific knockout tumor mouse models. The advantage of these models is that the growth process of tumors undergoes immune tolerance, immune editing, and immunity In the process of suppression, the final TME will be closer to the native state. However, due to the long time of tumor formation, differences in heterogeneity will lead to large differences in experimental results between mice, and the repetition rate is lower than that of homologous tumor models.

Carcinogen-Induced Tumor Models

Common carcinogen-induced tumor mouse models include DEN-induced liver cancer, MCA-induced fibrosarcoma, ultravolet B-induced skin cancer, NHK-induced lung cancer models, etc. These tumor models have obvious genomic instability and tumor formation time It is also about half a year to 1 year. Compared with the gene-edited tumor mouse model, it has a richer gene mutation spectrum. These mutations are involved in immune remodeling in the neoantigen process for a long time in the tumorigenesis process, and can more naturally simulate tumor immune microbes. The formation of the environment, and therefore, the tumor heterogeneity between mice is greater, and the results will be quite different.

PDX model (Patient-Derived Xenograft Models)

The PDX model refers to the direct inoculation of patient-derived tumor mass into mice subcutaneously or orthotopic transplantation. The advantage of this model is that it can retain the cellular composition of the patient’s tumor, the tumor immune microenvironment, and the genetic heterogeneity. Compared with the previous tumor formation methods, the results of immunotherapy are closer to the actual clinical treatment situation.

Before tumorigenesis, mice will undergo humanized remodeling of the immune system, usually in two ways:

One is to transplant the patient’s CD34+ HSC cells 10-14 weeks before vaccination. Hematopoietic stem cells will differentiate into the human immune cell lineage during this time. The advantage of this method is that there is no GVHR, but the waiting cycle after transplantation will be biased. Long, the evaluation of the effects of vaccination and subsequent immunotherapy cannot be carried out immediately, but the results will be more realistic.

Another way is to transplant the patient’s PBMC for immune remodeling, but because the T cells in PBMC are already mature T cells, there will be a certain degree of GVHR response after transplantation into mice, which will have a certain impact on the treatment results, but The advantage is that mice can be inoculated immediately after transplantation and the experiment can be started.

Summary

The above are several tumor mouse models commonly used in evaluating tumor immunotherapy. These models have their own advantages and disadvantages. If there are clinical sample resources, the PDX model is recommended first. This model can simulate the real immune microenvironment to the greatest extent; if the sample resources are not easy to obtain, from the experimental cycle and experimental risk From a perspective, we can give priority to a mouse model of a homologous tumor or a mouse model of a heterogeneous tumor. The preliminary results are obtained first, and the results are good, and there is ample time. If you need to get data closer to the clinical results, you can do gene-edited tumor mice. Model or carcinogen-induced tumor mouse model verification, or find clinical resources to make PDX models.

【references】

Daria S. Chulpanova et al. Mouse Tumor Models for Advanced Canc

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Syngeneic Mouse Models

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