CN113875690B - Lewis lung cancer mouse model based on tumor microenvironment and construction method thereof - Google Patents
Lewis lung cancer mouse model based on tumor microenvironment and construction method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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Abstract
The invention discloses a Lewis lung cancer mouse model based on a tumor microenvironment and a construction method thereof, belonging to the technical field of tumor models, wherein the Lewis lung cancer mouse model contains Lewis lung cancer cells, peripheral blood mononuclear cells and fibroblasts, wherein the ratio of the Lewis lung cancer cells to the peripheral blood mononuclear cells is (1-15): 1.
Description
Technical Field
The invention relates to the technical field of tumor models, in particular to a Lewis lung cancer mouse model based on a tumor microenvironment and a construction method thereof.
Background
At present, the lung cancer is at the forefront in the morbidity and mortality of malignant tumors in China and all over the world, and is the first major malignant tumor threatening the health of human beings. Current treatments for lung cancer include approaches: surgery, radiation therapy, chemotherapy, targeting, immunotherapy, and the like. In recent years, the research on the tumor microenvironment mechanism (tumor immune microenvironment) has become a hot research direction.
The animal model becomes an important preclinical experimental model for researching tumor immunity mechanism and clinical treatment efficacy. Common animal models include ectopic transplantation animal model, orthotopic transplantation animal model, induced animal model and transgenic animal model.
The current common animal model conditions are shown in Table 1
TABLE 1 mouse model of common tumors
As is known, the Tumor Microenvironment (TME) is composed of various cell components such as tumor cells, extracellular matrices (ECMs), tumor-associated fibroblasts (CAFs), endothelial cells, immune cells, and blood vessels, and plays an important role in tumor proliferation, invasion, metastasis, angiogenesis, metabolism, immunosuppression, drug resistance, and the like.
Tumor Infiltrating Lymphocytes (TILs) are a heterogeneous lymphocyte population within the TME, mainly comprising T cells, B cells, Dendritic Cells (DCs), natural killer cells (NK), macrophages, etc. Among them, T lymphocytes are mainly of three subtypes: CD8+, CD4+, regulatory T cells (Treg cells). The human immune system consists of Dendritic Cells (DC), natural killer cells (NK), CD8+ T cells, regulatory T cells (Treg), tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and the like.
At present, animal models are more commonly used: the ectopic transplantation animal model has the obvious defects that: the tumor tissue had less infiltrating lymphocytes and the tumor tissue had less abundant blood vessels, as shown in fig. 1.
As can be seen from the comparison of FIG. 1, the current lung cancer mouse model cannot truly simulate the tumor microenvironment of a lung cancer patient, and is not compelling to the research result of the tumor immune mechanism.
Therefore, it is highly desirable to construct a mouse model that is closest to the tumor immune microenvironment of tumor patients.
Disclosure of Invention
One of the objectives of the present invention is to provide a Lewis lung cancer mouse model based on tumor microenvironment to solve the above problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a Lewis lung cancer mouse model based on a tumor microenvironment contains Lewis lung cancer cells, peripheral blood mononuclear cells and fibroblasts, wherein the ratio of the number of the Lewis lung cancer cells to the number of the peripheral blood mononuclear cells is (1-15): 1.
As a preferred technical scheme: the ratio of the number of Lewis lung cancer cells to the number of peripheral blood mononuclear cells is 5: 1.
In the application, unless otherwise specified, the above ratio refers to the ratio of the numbers of LLC cells and PBMC cells, and at present, only tumor cells are injected into the existing transplanted tumor model, and in order to better simulate the in situ tumor microenvironment and increase the tumor formation rate, the invention constructs the above model, and the inoculation of the mixture of the three is the invention of the application, and the specific ratio is only one of the verification results of the present project. Among them, LLC, PBMC and L929 were mixed in a ratio of 5:1, L929 being 1X10 as described later, and LLC, PBMC and L929 were found to be most effective 5 And (4) respectively.
The second purpose of the invention is to provide a construction method of the Lewis lung cancer mouse model based on the tumor microenvironment, which adopts the technical scheme that: inoculating the Lewis lung cancer cells, the peripheral blood mononuclear cells and the fibroblasts into the mouse according to the proportion to obtain the mouse.
As a preferable technical scheme: the mouse is a C57BL/6 male mouse, is 6-8 weeks old and has the weight of 20-22 g.
Peripheral Blood Mononuclear Cells (PBMC), Lewis lung carcinoma cells (LLC), fibroblasts (L929)
Compared with the prior art, the invention has the advantages that: the Lewis lung cancer mouse model constructed by the invention can construct an immune microenvironment which is closer to that of a tumor patient in a mouse body, thereby providing a more appropriate, more accurate and more effective model for the mechanism research of tumor treatment.
Drawings
FIG. 1 is a comparison of prior art Lewis mouse model and lung cancer patient tissue scans;
FIG. 2 is a model construction technique roadmap for the present invention;
FIG. 3 is a graph showing the change of the tumor formation rate of each group of mice at different times;
FIG. 4 is a volume-size variation curve of a Lewis lung cancer transplanted tumor;
figure 5 is the mouse graft tumor volume at the end of the experiment (mean ± SD);
FIG. 6 is a bar graph (mean. + -. SD) of changes in the size of Lewis lung carcinoma transplantable tumors;
FIGS. 7-9 show the results of peripheral blood effector T cell expression in different groups of tumor-bearing mice;
FIGS. 10-11 show the results of Treg cell expression in peripheral blood of tumor-bearing mice in different groups
FIG. 12 shows the HE staining results of different groups of tumor-bearing mice;
FIG. 13 is a scanning electron micrograph (X200) of immunohistochemical FAP α of different groups of tumor-bearing mice;
FIG. 14 is a graph comparing the percent of immunohistochemical FAP α in different groups of tumor-bearing mice;
FIGS. 15-17 are multiple immunofluorescence plots for different groups of tumor-bearing mice;
FIG. 18 is a graph showing the results of immunofluorescence CD8+ in different groups of tumor-bearing mice;
FIG. 19 is a graph showing the results of immunofluorescence CD39+ in different groups of tumor-bearing mice;
FIG. 20 is a graph showing immunofluorescence PD-1 results for different groups of tumor-bearing mice;
FIGS. 21-23 are graphs showing the volume change of tumors in different groups of tumor-bearing mice after radiotherapy;
FIG. 24 is a graph of the percentage of CD4 cells/CD 3 cells radioactively treated in different groups of tumor-bearing mice;
FIG. 25 is a graph of the percentage of CD8 cells/CD 3 cells radioactively treated in different groups of tumor-bearing mice;
FIG. 26 shows CD8, CD39, and PD1 expression in different tumor tissues.
Detailed Description
The invention will be further explained with reference to the drawings.
Example 1
A method for constructing Lewis lung cancer mouse model based on tumor microenvironment is shown in FIG. 2, wherein the Lewis lung cancer mouse model contains Lewis lung cancer cell (LLC), Peripheral Blood Mononuclear Cell (PBMC) and fibroblast (L929 is selected as fibroblast in this embodiment),
cell line: lewis lung cancer cell (LLC), fibroblast (L929)
Experimental animals: maternal homologous inbred C57BL/6 male mice, 6-8 weeks old, weighing 20-22 g.
Depending on whether the source is grouped, 6 per group, as follows,
group A: LLC + PBMC (inactivated lymphocyte)
Group B: LLC + PBMC (inactivated lymphocyte) + L929
Group C: LLC + PBMC (LLC: 1. the main points of the design reside in the PBMC)
Group D: LLC + PBMC + L929(LLC: PBMC ═ 1:1)
Group E: LLC + PBMC (LLC: PBMC ═ 5:1)
And F group: LLC + PBMC + L929(LLC: PBMC 5:1)
Group G: LLC + PBMC (LLC: 10: 1. the main points of the design reside in the PBMC.)
Group H: LLC + PBMC + L929(LLC: 10:1 PBMC)
In each group, the number of LLC cells inoculated to each mouse was 5X 10 5 1X10 cells in all L929 cells 5 The ratios described are ratios of cell numbers between LLC and PBMC, e.g. "LLC: PBMC ═ 1: 1" in group C, meaning that LLC cells count 5X 10 5 The number of PBMCs is 5 multiplied by 10 5 A plurality of;
the method for inactivating the lymphocyte by using PBMC comprises the following steps: inactivating PBMC extracted from peripheral blood with mitomycin with concentration of 25 μ g/ml at 37 deg.C for 30 min;
on day 0, mice were inoculated subcutaneously with 0.1ml of different tumor cell suspensions in the right hind limb, and the mouse status, tumorigenesis and tumor volume were observed and recorded after tumor implantation. Tumor volume V (mm3) ═ axb 2/2. Tumor-bearing mice are treated 28 days after tumor inoculation, and a laboratory detection method is carried out, wherein the flow cytometry technology comprises the following steps: PBMCs were isolated from mouse peripheral eye blood and effector T cells (CD3+ CD8+, CD3+ CD4+ expression) and Treg cells (CD4+ CD25+, CD4+ FOXP3+ expression) were detected.
20 lung cancer patients, each group of tumor-bearing mice pathological tissue paraffin block sections:
HE staining: observation of pathological tissue structure (tumor cell, lymphocyte, blood vessel distribution)
Immunohistochemistry (SP method): fibroblast Activation Protein (FAP) expression in tumor tissue
Multiple immunofluorescence: observing and collecting images under a confocal microscope according to the expression conditions of CD8, CD39 and PD-1 in the tumor tissue, and analyzing the results by imageJ software;
all experimental data were plotted and analyzed using Graph Pad Prism 8.0 software. Data are presented as mean ± SD. The statistical differences between the two groups were tested by Student's t and were statistically significant with P < 0.05.
The experimental results are as follows:
(1) the change curve of the tumor formation rate of each group of mice at different time is shown in figure 3, the change curve (mean value +/-SD) of the size of Lewis lung cancer transplanted tumor is shown in figure 4, and the LLC + PBMC (inactivated lymphoma) + L929 forms the fastest tumor and the largest tumor size; 1:1LLC + PBMC resulted in the slowest tumor formation and the smallest tumor volume.
(2) The volume of the mouse transplanted tumor (mean + -SD) at the end of the experiment is shown in figure 5, the histogram of the change of the size of the Lewis lung cancer transplanted tumor (mean + -SD) is shown in figure 6, and the LLC + PBMC (inactivated lymphoma) + L929 group tumor has larger volume and statistical significance compared with the LLC + PBMC (inactivated lymphoma) (P < 0.01); 1:1LLC + PBMC group has small tumor volume and statistical significance (P <0.001), and in tumor-bearing mice, mixed cell suspension containing L929 can promote tumor growth after tumor inoculation, and cell suspension containing lymphocyte can inhibit tumor growth.
Example 2
Radiotherapy verification:
the method comprises the following steps: 16 male C57BL/6 mice of 6-8 weeks old and 20-22g are divided into 4 groups according to whether the mice are homologously grouped, the specific groups are as follows,
group A: LLC + PBMC (inactivated lymphocyte)
Group B: LLC + PBMC (inactivated lymphocyte) +8Gyx3f RT
Group C: LLC + PBMC + L929(LLC and PBMC optimal proportion)
Group D: LLC + PBMC + L929(LLC and PBMC optimal proportion) +8Gyx3f RT
After 2 weeks of tumor implantation, 8Gyx3f radiation therapy was performed every other day, and changes in volume of each group were observed.
On the 2 nd day after the radiotherapy is finished, the change of the number of CD3+ CD4+ T, CD3+ CD8+ T lymphocytes and CD4+ CD25+, CD4+ FOXP3+ Treg cells in the peripheral blood of each group of tumor-bearing mice is analyzed by a flow cytometer.
The experimental results are as follows:
(1) the results of peripheral blood effector T cell expression in different groups of tumor-bearing mice are shown in FIGS. 7-9, from which it can be seen that: 5:1LLC + PBMC + L929 tumor-bearing mice have higher peripheral blood CD3+ CD4+ T, CD3+ CD8+ T cell number than LLC + PBMC (inactivated lymphoma) group, and have statistical significance.
(2) The expression results of the peripheral blood effector Treg cells of different groups of tumor-bearing mice are shown in the figures 10-11, and the numbers of the peripheral blood CD4+ CD25+, CD4+ Fxop3+ Treg cells of the 5:1LLC + PBMC + L929 group of tumor-bearing mice are higher than those of the LLC + PBMC (inactivated lymphocyte) group, so that the statistical significance is achieved.
Example 3
HE staining test:
the HE staining results for different groups of tumor-bearing mice are shown in fig. 12, from which it can be seen that: PBMC in the tumor mixed suspension can increase the number of lymphocytes infiltrated in tumor tissues of tumor-bearing mice; the fibroblast L929 in the tumor mixed suspension can promote the generation of blood vessels in tumor tissues of tumor-bearing mice; 5:1LLC + PBMC + L929 experimental group is closer to lung cancer patients in tumor tissue structure under the microscope, and shows abundant tumor infiltrating lymphocytes and abundant blood vessels which are more similar to the cells of the lung cancer patients.
Example 4
Immunohistochemical FAP assay:
fibroblast Activation Protein (FAP) is a specific marker of tumor-associated fibroblasts (CAFs), and high-expression FAP in tumor tissues can promote Treg cells and tumor-associated macrophages (TAM) to generate immune escape, participate in generation of tumor blood vessels, and play an important role in generation, development, invasion and metastasis of tumors.
The test results are shown in fig. 13 and fig. 14, and it can be seen from the graphs that the expression of FAP is higher in the tumor tissue of the tumor-bearing mice containing fibroblast L929 in the inoculated tumor mixed suspension, and further, it can be seen that the expression of FAP is increased in the group containing L929 in the inoculated mixed solution; in FIG. 13, the number of L929 inoculated was 1X10 regardless of the ratio of LLC to LY (lymphocytes in monocytes) 5 Although slightly different in expression, the expression of the protein is compared with that of a common modelHas significant difference and is closer to tumor patients.
Example 5
Multiplex immunofluorescence CD8, CD39, PD-1 assays
The test results are shown in FIGS. 15, 16, 17, 18, 19 and 20,
as can be seen from the figure, the expression of CD8, CD39 and PD-1 in the tumor tissues of the 5:1LLC + lymphocyte + L929) experimental group and the lung cancer patients has statistical significance compared with the expression of LLC + PBMC (inactivated lymphocyte) of the control group, and further, the expression of CD8, CD39 and PD-1 in the 5:1LLC + lymphocyte + L929) is similar to that of the lung cancer patients, so that the tumor immune microenvironment of the lung cancer patients can be simulated better.
Example 6
Radiotherapy verification test: 8Gy x3f on alternate days,
(1) change in tumor volume
The results are shown in FIGS. 21-23, from which it can be seen that for 5:1LLC + PBMC + L929, the tumor volume of the radiotherapy group grew more slowly than that of the non-radiotherapy group, which is statistically significant; LLC + PBMC (inactivated lymphocyte) showed no significant difference in tumor volume between the two groups.
It can be seen that the tumor inhibition effect of radiotherapy on 5:1LLC + PBMC + L929 is obviously better than that of LLC + PBMC (inactivated lymphoma).
(2) The percentage of CD4 cells/CD 3 cells radioactively treated by different groups of tumor-bearing mice and the percentage of CD8 cells/CD 3 cells radioactively treated by different groups of tumor-bearing mice
The results are shown in FIGS. 24 and 25, from which it can be seen that the number of CD3+ CD4+ T cells in peripheral blood lymphocytes decreased (P <0.001) and the number of CD3+ CD8+ T cells increased (P <0.001) after radiation treatment in LLC + PBMC + L929(5:1) group of tumor-bearing mice; the number of CD3+ CD4+ T cells in LLC + PBMC (inactivated lymphocyte) group was significantly reduced (P <0.001), and no significant difference was observed in the number of CD3+ CD8+ T cells.
CD8, CD39 and PD-1 are important indexes of response to immune activation or immune suppression, and as can be seen from FIG. 26, the expression of CD8, CD39 and PD-1 in the novel model, namely the LLC + PBMC + L929(5:1) group, is closer to that of a lung cancer patient.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (3)
1. A method for constructing a Lewis lung cancer mouse model based on a tumor microenvironment is characterized by comprising the following steps: the Lewis lung cancer mouse model contains Lewis lung cancer cells, peripheral blood mononuclear cells and fibroblasts, wherein the ratio of the number of the Lewis lung cancer cells to the number of the peripheral blood mononuclear cells is (1-15) to 1, and the construction method comprises the following steps: inoculating the Lewis lung cancer cells, the peripheral blood mononuclear cells and the fibroblasts into the mouse according to the proportion to obtain the mouse.
2. The method of claim 1, wherein: the ratio of the number of Lewis lung cancer cells to the number of peripheral blood mononuclear cells is 5: 1.
3. The method of claim 1, wherein: the mouse is a C57BL/6 male mouse, is 6-8 weeks old and has the weight of 20-22 g.
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