CN112501291A - Application of NAMPT in preparation of kit for predicting sensitivity of solid tumor patient to immune checkpoint inhibitor therapy - Google Patents
Application of NAMPT in preparation of kit for predicting sensitivity of solid tumor patient to immune checkpoint inhibitor therapy Download PDFInfo
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Abstract
The invention relates to the field of clinical molecular diagnosis, in particular to application of NAMPT in preparation of a kit for predicting sensitivity of a solid tumor patient to immune checkpoint inhibitor therapy. According to the invention, through in vitro experiments, the expression of PD-L1, one of key indexes of prediction of the curative effect of an immune checkpoint inhibitor induced by interferon gamma, can be down-regulated by knocking down various tumor cells NAMPT; further, in vivo experiments show that the NAMPT normally expresses the liver cancer model and has obvious treatment effect on the anti-PD-L1 antibody; the NAMPT knockdown expression liver cancer model is insensitive to the anti-PD-L1 antibody treatment reaction, and the tumor growth is not obviously inhibited, which indicates that the NAMPT knockdown expression tumor is resistant to the immune checkpoint inhibitor. The invention provides a new prediction index for the curative effect of the tumor on the immune checkpoint inhibitor.
Description
Technical Field
The invention relates to the field of clinical molecular diagnosis, in particular to Nicotinamide Adenine Dinucleotide (NAD)+) Use of the expression level of nicotinamide phosphoribosyltransferase (NAMPT), a synthesis rate-limiting enzyme, for predicting the sensitivity of a solid tumor patient to immune checkpoint inhibitor therapy.
Background
In recent years, significant progress has been made in improving survival in patients with advanced lung cancer, melanoma, renal cancer, Hodgkin lymphoma, etc. (Ribas A, Wolchok JD. cancer immunological use checkpoint. science,2018,359: 1350-. Among them, immune checkpoint inhibitors targeting programmed cell death receptor 1(PD-1) or ligand (PD-L1) are of great interest for their significant clinical efficacy, including anti-PD-1 antibodies: nivolumab (Opdivo) and pembrolizumab (Keytruda), anti-PD-L1 antibody: and the like. Although immune checkpoint inhibitors have shown significant therapeutic efficacy in clinical applications, their low efficacy in solid tumors is a very significant limitation. Therefore, the search for effective therapeutic effect prediction markers is an important method for improving tumor immunotherapy effects and promoting tumor precise immunotherapy (Gibney GT, Weiner LM, Atkins MB. predictive biological markers or checkpoint inhibitors-based immunotherapy, 2016,17: e542-e 551). There is increasing evidence that patients with tumor cancers with high expression of PD-L1 could obtain better therapeutic efficacy from anti-PD-1/PD-L1 antibodies (ref M, Rodri i guez-Abreu D, Robinson AG, Hui R,
T,
A,Gottfried M,Peled N,Tafreshi A,Cuffe S,O'Brien M,Rao S,Hotta K,Leiby MA,Lubiniecki GM,Shentu Y,Rangwala R,Brahmer JR；KEYNOTE-024Investigators.Pembrolizumab versus chemotherapy for PD-L1-positive nonsmall-cell lung cancer.N.Engl.J.Med.,2016,375:1823-1833.)。
nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD +) biosynthetic pathway, also known as Visfatin (Visfatin) or pre-B cell clonogenic enhancer factor (PBEF). NAMPT affects many processes, including metabolism, inflammation, cell proliferation, differentiation and apoptosis, especially cell aging, mainly by modulating the level of NAD + in the body or cells (literature: Garten, A., Schuster, S., Penke, M., Gorski, T., de Giorgis, T., and Kiess, W. (2015.) Physiological and Physiological roles of NAMPT and NAD metabolism, Nat. Rev. Endocrinol.11, 535-546.). In recent years, NAMPT has been found to be highly expressed in a variety of malignant tumors and is closely related to the occurrence, development and treatment of malignant tumors (Gujar, A.D., Le, S., Mao, D.D., Dadey, D.Y., Turski, A., Sasaki, Y., Aum, D.D., Luo, J.Dahiya, S., Yuan, L.et al. (2016.) An NAD + -dependenttransection promoter genes self-renewal and radiation resistance in gliobasto.Natl.Acad.Sci.USA 113, E8247-E8256. lucena-Cacal, A., o-alcohol, D.J., Jim-Garci.P.P.,
S.,and Carnero,A.(2018).NAMPT is a potent oncogene in colon cancer progression that modulates cancer stem cell properties and resistance to therapy through Sirt1 and PARP.Clin.Cancer Res.24,1202-1215.)。
disclosure of Invention
The invention aims to apply tumor tissue NAD+Expression levels of the synthetic rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) predict susceptibility of solid tumor patients to immune checkpoint inhibitor therapy.
In a first aspect of the invention, there is provided the use of nicotinamide phosphoribosyltransferase (NAMPT) for the preparation of a kit for predicting the sensitivity of a patient with a solid tumor to treatment with an immune checkpoint inhibitor.
Further, the kit detects the expression level of NAMPT of a patient with solid tumor.
Further, in said use, NAMPT low expressing tumors are insensitive to immune checkpoint inhibitors.
Furthermore, in the application, the patient with normal expression and high expression of NAMPT has higher benefit rate and better response to the treatment of the immune checkpoint inhibitor.
In a second aspect of the invention, there is provided the use of nicotinamide phosphoribosyltransferase (NAMPT) in the preparation of a kit for predicting the expression level of induced PD-L1 in a patient with a solid tumor.
Further, in the application, the higher the expression of NAMPT, the higher the expression of inducible PD-L1.
Further, the immune checkpoint inhibitor is an immune checkpoint inhibitor targeting programmed cell death receptor 1(PD-1) or ligand (PD-L1); including anti-PD-1 antibodies: nivolumab (Opdivo) and pembrolizumab (Keytruda), anti-PD-L1 antibody: and the like.
In a third aspect of the invention, there is provided a kit for predicting the sensitivity of a solid tumor patient to an immune checkpoint inhibitor therapy by detecting the expression level of NAMPT in the solid tumor patient. NAMPT low expressing tumors were insensitive to immune checkpoint inhibitors; the patient with normal expression and high expression of NAMPT has higher benefit rate and better response to the treatment of the immune checkpoint inhibitor.
Furthermore, the kit detects the expression levels of NAMPT genome, mRNA and protein in tumor tissues and serum of patients with solid tumors.
Furthermore, the tumor is pancreatic cancer, lung cancer, liver cancer, melanoma and the like.
The invention discovers that the NAMPT expression level of tumor cells can predict the sensitivity of tumors to immune checkpoint inhibitor therapy from the research of in vitro cell culture and in vivo animal experiments. Through in vitro experiments, the knocking-down of various tumor cells NAMPT can down-regulate PD-L1 expression which is one of key indexes for predicting the curative effect of an immune checkpoint inhibitor induced by interferon gamma; further, in vivo experiments show that the NAMPT normally expresses the liver cancer model and has obvious treatment effect on the anti-PD-L1 antibody; the NAMPT knockdown expression liver cancer model is insensitive to the anti-PD-L1 antibody treatment reaction, and the tumor growth is not obviously inhibited, which indicates that the NAMPT knockdown expression tumor is resistant to the immune checkpoint inhibitor.
The invention provides a new prediction index for the sensitivity of tumors to immune checkpoint inhibitor therapy.
Drawings
FIG. 1: and (3) detecting the expression level of PD-L1 mRNA induced by interferon gamma after the mouse lung cancer cell line LLC (A), the mouse melanoma cell B16(B), the mouse liver cancer cell line Hepa1-6(C) and the human liver cancer cell line Huh7(D) are expressed by knocking down NAMPT through small interfering RNA by real-time fluorescent quantitative PCR. The experimental data are expressed as mean soil standard deviation (mean ± SD). Denotes p value <0.05, denotes p value < 0.01.
FIG. 2: comparison of tumor volumes between control and anti-PD-L1 antibody treated groups; wherein A is NAMPT normal expression liver cancer model, B is NAMPT knockdown expression liver cancer model. The experimental data are expressed as mean soil standard deviation (mean ± SD). n.s. indicates no statistical difference, indicates a p value < 0.001.
FIG. 3: the benefit rate of anti-PD-1 antibody treatment after grouping of 33 melanoma patients according to NAMPT high-low expression.
Detailed Description
The following examples are provided to illustrate specific embodiments of the present invention.
Example 1: tumor cell NAMPT expression levels affect inducible PD-L1 expression.
The experimental method comprises the following steps: the method comprises the steps of firstly using small interfering RNA to knock down NAMPT expression of a mouse lung cancer cell line LLC, a mouse melanoma cell B16, a mouse liver cancer cell line Hepa1-6 and a human liver cancer cell line Huh7 respectively, then inoculating the NAMPT knock-down expression cells and corresponding normal cells into a six-well cell culture plate, adding 100ng/ml interferon gamma or equivalent corresponding solvent as a control when the cell density is about 50%, stimulating for 24 hours, collecting cell RNA, and detecting the change of the PD-L1 transcription level.
As a result: as shown in FIGS. 1A-D, after 100ng/ml interferon gamma was added, the expression level of PD-L1 of NAMPT knockdown expression cells was significantly lower than that of control cells which are normally expressed by NAMPT, which indicates that the expression level of NAMPT affects the expression of PD-L1 induced by interferon gamma, and the higher the expression of NAMPT of tumor cells is, the higher the expression of inducible PD-L1 of tumor cells is.
Example 2: knockdown of NAMPT expression led to the tolerance of immunotherapy-sensitive tumors to anti-PD-L1 antibody treatment.
The experimental method comprises the following steps: 1X 106The NAMPT knockdown expression liver cancer Hepa1-6 cells and corresponding NAMPT normal cells are respectively inoculated under hind limb skin of 6-8 week-old male C57BL/6 mice, after one week, mouse tumor models of the two cells are respectively randomly divided into a treatment control group and an anti-PD-L1 antibody group, each group comprises 5 anti-PD-L1 antibodies: intraperitoneal injection is carried out 2 times per week (100 mug/mouse), and the tumor volume is measured every 3 days (the tumor volume is calculated according to the formula: 1/2 x tumor long diameter x short diameter)2)。
As a result: after two weeks of group treatment, as shown in fig. 2A, the NAMPT normal expression liver cancer model has an obvious therapeutic effect on the anti-PD-L1 antibody, and the tumor growth is significantly inhibited; however, as shown in fig. 2B, the NAMPT-knockdown expression liver cancer model was insensitive to anti-PD-L1 antibody treatment response, and tumor growth was not significantly inhibited, indicating that NAMPT-knockdown tumors were resistant to immune checkpoint inhibitors.
Example 3: patients with NAMPT-high expressing tumors were more responsive to immune checkpoint inhibitors.
The experimental method comprises the following steps: based on tumor NAMPT expression levels, 33 melanoma patients (GSE91061) treated with anti-PD-1 antibody were first divided into two groups of high (n-11) and low (n-22) NAMPT expression, and then the treatment benefit was analyzed in both groups.
As a result: partial or complete remission was obtained after anti-PD-L1 antibody treatment in 6 of 11 patients with high NAMPT expression, while only 4 of 22 patients with low NAMPT expression benefited. Therefore, patients with high NAMPT expression have higher benefit rate and better response to the treatment of the immune checkpoint inhibitor.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full range of equivalents.
Claims (10)
- Use of NAMPT in the preparation of a kit for predicting the sensitivity of a solid tumor patient to immune checkpoint inhibitor therapy.
- 2. The use of claim 1, wherein the kit detects the expression level of NAMPT in a patient with a solid tumor.
- 3. The use of claim 2, wherein the NAMPT-low expressing tumor is insensitive to immune checkpoint inhibitors.
- 4. The use of claim 2, wherein the normal and high expression NAMPT patients benefit from and respond better to treatment with immune checkpoint inhibitors.
- Use of NAMPT in the preparation of a kit for predicting the expression level of induced PD-L1 in a patient with a solid tumor.
- 6. The use of claim 5, wherein the higher the expression of NAMPT, the higher the expression of inducible PD-L1.
- 7. The use of any one of claims 1 to 6, wherein the immune checkpoint inhibitor is an immune checkpoint inhibitor that targets programmed cell death receptor 1 or a ligand.
- 8. A kit for predicting the sensitivity of a solid tumor patient to an immune checkpoint inhibitor therapy by detecting the expression level of NAMPT in a solid tumor patient.
- 9. The kit of claim 8, wherein the kit detects the expression levels of NAMPT genome, mRNA and protein in tumor tissue and serum of a patient with solid tumor.
- 10. The kit of claim 8, wherein the tumor is pancreatic cancer, lung cancer, liver cancer, melanoma.
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| CN114184790A (en) * | 2022-01-13 | 2022-03-15 | 中国人民解放军海军军医大学第一附属医院 | Application of BGN gene in prediction of treatment effect of immune checkpoint inhibitor of colon cancer patient |
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| WO2019134946A1 (en) * | 2018-01-04 | 2019-07-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
| WO2019173456A1 (en) * | 2018-03-06 | 2019-09-12 | Board Of Regents, The University Of Texas System | Replication stress response biomarkers for immunotherapy response |
| WO2020191359A1 (en) * | 2019-03-21 | 2020-09-24 | Fred Hutchinson Cancer Research Center | Cancer combination therapies utilizing a nicotinamide phosphoribosyltransferase inhibitor in combination with a nicotinamide adenine dinucleotide salvage pathway precursor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019134946A1 (en) * | 2018-01-04 | 2019-07-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
| WO2019173456A1 (en) * | 2018-03-06 | 2019-09-12 | Board Of Regents, The University Of Texas System | Replication stress response biomarkers for immunotherapy response |
| WO2020191359A1 (en) * | 2019-03-21 | 2020-09-24 | Fred Hutchinson Cancer Research Center | Cancer combination therapies utilizing a nicotinamide phosphoribosyltransferase inhibitor in combination with a nicotinamide adenine dinucleotide salvage pathway precursor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114184790A (en) * | 2022-01-13 | 2022-03-15 | 中国人民解放军海军军医大学第一附属医院 | Application of BGN gene in prediction of treatment effect of immune checkpoint inhibitor of colon cancer patient |
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