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Use of acyl-CoA:cholesterol acyltransferase Acat1 inhibitors

A kind of use and tumor technology, applied in the field of acyl-CoA:cholesterol acyltransferase ACAT1 inhibitors, can solve the problems of undisclosed association, achieve the effect of enhancing immune response, enhancing activation, and enhancing CD8 T cell immune response ability

Active Publication Date: 2021-06-22
CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the prior art does not disclose the association between ACAT1 and tumor immunotherapy

Method used

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  • Use of acyl-CoA:cholesterol acyltransferase Acat1 inhibitors
  • Use of acyl-CoA:cholesterol acyltransferase Acat1 inhibitors
  • Use of acyl-CoA:cholesterol acyltransferase Acat1 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0266] Example 1 Inhibition of cholesterol esterification can enhance the effector function of CD8 T cells

[0267] Test method: The cells obtained by magnetic bead sorting were resuspended in RPMI 1640 complete medium, and the corresponding concentration of inhibitors was added, and the cells were incubated at 37 degrees CO 2 Cultured in the incubator for 6 hours, then washed 3 times with RPMI 1640 complete medium, and finally resuspended in RPMI 1640 complete medium and transferred to the well plate with activating antibodies a-CD3 and a-CD28, 37 degrees CO 2 The culture was stimulated for 20 hours in the incubator, and then Brefeldin A (5ug / ml) was added to continue the culture for 4 hours to inhibit the secretion of cytokines. After the culture was over, the cells were collected, labeled with CD8 antibody surface, and then fixed with 4% paraformaldehyde at room temperature for 10 minutes. The cell membrane was punched with 0.1% Triton-X100, and the corresponding proteins i...

Embodiment 2

[0269] Example 2 T cell-specific knockout of ACAT1 enhances the immune response of CD8 T cells.

[0270] The purpose of this example is to verify the function of ACAT1 in CD8 T cells. ACAT1 flox / flox mouse with CD4 Cre The mice were mated to obtain T cell-specific knockout ACAT1 mice (CD4 Cre -Acat1 flox / flox , referred to as Acat1 CKO ) and corresponding wild-type control mice (Acat1 flox / flox ).

[0271] Ex vivo test method: CD8T cells obtained by magnetic bead sorting were resuspended in RPMI 1640 complete medium, and corresponding concentrations of inhibitors were added, and 37°C CO 2 Cultured in the incubator for 6 hours, then washed 3 times with RPMI 1640 complete medium, and finally resuspended in RPMI 1640 complete medium and transferred to the well plate with activating antibodies α-CD3 and α-CD28, 37 degrees CO 2 The culture was stimulated for 20 hours in the incubator, and then Brefeldin A (5 μg / ml) was added to continue the culture for 4 hours to inhibit the...

Embodiment 3

[0274] Example 3 ACAT1 Gene Knockout Promotes the Proliferation of CD8 T Cells and Reduces Apoptosis

[0275] The purpose of this example is to detect the effect of ACAT1 on the proliferation of CD8 T cells. Through CFSE labeling experiments, CD8 cells were stimulated with α-CD3+α-CD28 antibodies, and the effect of ACAT1 on the proliferation of CD8 T cells was further detected. Compared with wild-type CD8 T cells, Acat1 CKO The proliferation ability of CD8 T cells was enhanced ( image 3 .a). At the same time, the apoptosis of CD8 T cells after activation was detected by Annexin V and PI staining, and the results showed that Acat1 CKO CD8 T cell Annexin V - P.I. - Compared with wild-type cells, the proportion of viable cells increased significantly, while cells in apoptotic state (AnnexinV + P.I. - and AnnexinV + P.I. + ) was significantly reduced ( image 3 .b,c).

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Abstract

The present invention provides novel uses of inhibitors of acyl-CoA:cholesterol acyltransferase ACAT1. The invention discloses an acyl-CoA:cholesterol acyltransferase ACAT1 inhibitor that can enhance the immune response ability of CD8 T cells; enhance the killing activity of CD8 T cells on tumors; enhance the effector function of CD8 T cells; and promote the proliferation of CD8 T cells; Reduce the apoptosis of CD8 T cells; promote the clustering of T cell antigen receptors (TCR) on the plasma membrane of CD8 T cells; promote the directional release of cytotoxic granules from CD8 T cells; promote the formation of CD8 T cell immune synapse; think acyl-CoA : Cholesterol acyltransferase ACAT1 inhibitors can be used for tumor immunotherapy or to improve immunity against tumors.

Description

technical field [0001] The invention belongs to the field of biotechnology, in particular to a novel use of an acyl-coenzyme A:cholesterol acyltransferase ACAT1 inhibitor. Background technique [0002] Malignant tumors are currently one of the most lethal diseases. Conventional treatment methods such as surgical resection, radiotherapy and chemotherapy are widely used in tumor treatment. However, these methods have limitations in the treatment of tumors, and it is difficult to completely cure them. Tumors, especially some metastatic malignant tumors. [0003] Immunotherapy has always been a research hotspot in tumor treatment. Cytokines interleukin-2 (IL2) and interferon-α (IFNα) have been used in the treatment of renal cell carcinoma and melanoma for more than two decades, although the target specificity is weak and the toxicity is high. In recent years, with the application of anti-PD-1 and anti-CTLA-4 and other immune checkpoint blocking antibodies in tumor immunotherap...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K31/255A61K31/4164A61K31/44A61K31/496A61K39/395A61P35/00
CPCA61K31/255A61K31/4164A61K31/44A61K31/496A61K39/3955A61K45/00A61K2300/00
Inventor 许琛琦李伯良杨魏白轶冰熊缨
Owner CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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