Application of CD74 gene as molecular marker in preparation of bladder cancer immunotherapy curative effect prediction reagent
By detecting the expression level of the CD74 gene, the problem of individual differences in the efficacy of bladder cancer immunotherapy was solved, the accurate prediction of the effect of bladder cancer immunotherapy was achieved, and the targetedness and effectiveness of the treatment were improved.
Patent Information
- Application Number
- CN202511180392.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-22
- Publication Date
- 2025-10-03
AI Technical Summary
The efficacy of bladder cancer immunotherapy varies depending on individual patient differences and disease stage. The lack of effective efficacy prediction markers leads to problems of drug resistance and individual differences.
Using the CD74 gene as a molecular marker, the expression level of the CD74 gene in patient samples is detected to predict the efficacy of bladder cancer immunotherapy, especially the therapeutic effect of PD-1/PD-L1 inhibitors. High expression of the CD74 gene indicates a better treatment response.
The expression level of the CD74 gene can accurately predict the effect of bladder cancer immunotherapy, help formulate personalized treatment plans, improve the targetedness and effectiveness of treatment, and reduce drug resistance.
Smart Images
Figure CN120733041A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical technology, and in particular to the use of the CD74 gene as a molecular marker in the preparation of a reagent for predicting the efficacy of bladder cancer immunotherapy. Background Art
[0002] Immunotherapy has demonstrated significant potential and efficacy in the treatment of bladder cancer, becoming a significant breakthrough in cancer treatment in recent years. By activating the patient's own immune system to identify and attack cancer cells, immunotherapy provides a powerful supplement to traditional treatments such as surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibitors (such as PD-1 / PD-L1 inhibitors) have been particularly effective in the treatment of advanced bladder cancer, significantly prolonging patient survival and improving quality of life. These drugs work by blocking tumor cells' suppression of the immune system and restoring the anti-tumor activity of T cells, thereby achieving a precise attack on cancer cells.
[0003] The advantages of immunotherapy lie in its highly targeted nature and relatively minimal side effects, offering new hope for patients who cannot tolerate traditional treatments or are resistant to chemotherapy. However, the efficacy of bladder cancer immunotherapy varies depending on individual patient differences and disease stage, and challenges such as drug resistance and individual variability remain. Therefore, a biomarker that can reflect the efficacy of bladder cancer immunotherapy is urgently needed. Summary of the Invention
[0004] The purpose of the present invention is to provide the use of CD74 gene as a molecular marker in the preparation of a reagent for predicting the efficacy of bladder cancer immunotherapy.
[0005] The present invention solves the technical problem by adopting the following technical solutions: In a first aspect, the present invention provides the use of a CD74 agonist in the preparation of a drug for treating bladder cancer. A 2025 article published in the journal Developmental Cell ("A subset of neutrophils activates anti-tumor immunity and inhibits non-small-cell lung cancer progression") synthesized a CD74 agonist (5A, an agonist for CD74).
[0006] In a second aspect, the present invention provides the use of the CD7 gene as a molecular marker in the preparation of a reagent for predicting the efficacy of bladder cancer immunotherapy.
[0007] In one or more embodiments of the present invention, the efficacy of bladder cancer immunotherapy is predicted by detecting the expression level of CD74 gene in patient samples. The higher the expression level of CD74 gene, the better the efficacy of bladder cancer immunotherapy.
[0008] In one or more embodiments of the present invention, the CD74 gene is used as a molecular marker in the preparation of a reagent for predicting the efficacy of PD-1 / PD-L1 inhibitors in treating bladder cancer.
[0009] In one or more embodiments of the present invention, the efficacy of PD-1 / PD-L1 inhibitors in treating bladder cancer is predicted by detecting the expression level of CD74 gene in patient samples. The higher the expression level of CD74 gene, the better the efficacy of PD-1 / PD-L1 inhibitors in treating bladder cancer.
[0010] In one or more embodiments of the present invention, the CD74 gene is a protein encoded by the CD74 gene.
[0011] In one or more embodiments of the present invention, the PD-1 / PD-L1 inhibitor includes pembrolizumab, atezolizumab, nivolumab or biosimilars thereof.
[0012] The CD74 gene is located on human chromosome 5q33.1. In a mouse subcutaneous bladder cancer model, knocking down CD74 expression promotes tumor growth and progression, suggesting that CD74 inhibits the development and progression of bladder cancer.
[0013] CD74 can be used as a marker for bladder cancer immunotherapy, and bladder cancer patients with high CD74 expression have a better response to immunotherapy. In addition, CD74 expression is positively correlated with the expression of PD1 (PDCD1) and PDL1 (CD274).
[0014] The above results indicate that CD74 inhibits the occurrence and development of bladder cancer and serves as a marker for bladder cancer immunotherapy.
[0015] The present invention includes the following beneficial effects: 1. By using a CD74 knockdown bladder cancer cell line to establish a bladder cancer subcutaneous tumor model, CD74 expression can promote the growth and development of bladder cancer tumors, indicating that CD74 inhibits the occurrence and development of bladder cancer.
[0016] 2. Bioinformatics analysis of bladder cancer tissue transcriptome data (TCGA-BLCA) revealed that high expression of CD74 in bladder cancer is positively correlated with PDCD1 and CD274 expression, and is associated with a better prognosis. This suggests that CD74 could be used as a biomarker for bladder cancer immunotherapy. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1This is the KM survival curve analysis of the transcriptome data of 359 bladder cancer tissues (TCGA-BLCA) in Example 1.
[0018] Figure 2 This is the forest plot multivariate Cox regression analysis of Example 1 for CD74 expression, gender, and bladder cancer stage.
[0019] Figure 3 For Example 1, 359 bladder cancer tissues were divided into two groups: CD74 high expression group and CD74 low expression group, and the expression of PDCD1 and CD274 in the two groups was compared.
[0020] Figure 4 This is a correlation analysis diagram of the expression of CD74, PDCD1 and CD274 in Example 1.
[0021] Figure 5 This is the response index of anti-CTLA-4 and anti-PD-1 antibodies in the CD74 high and low expression groups in Example 1.
[0022] Figure 6 This is the KM survival curve analysis of the transcriptome data (ArrayExpress) of 478 bladder cancer tissues in Example 2.
[0023] Figure 7 The 478 bladder cancer tissues in Example 2 were divided into two groups: CD74 high expression group and CD74 low expression group, and the expressions of PDCD1 and CD274 in the two groups were compared.
[0024] Figure 8 This is the correlation analysis among the expressions of CD74, PDCD1 and CD274 in Example 2.
[0025] Figure 9 This is the tumor size on day 22 of inoculation of the bladder cancer subcutaneous tumor model in Example 3.
[0026] Figure 10 This is a line graph showing the changes in tumor size over time in the subcutaneous bladder cancer model in Example 3.
[0027] Figure 11 The tumor weight on the 22nd day after inoculation of the bladder cancer subcutaneous tumor model in Example 3.
[0028] Unless stated otherwise, the terms used in the specification and claims have the following meanings.
[0029] As used herein, the term "prevention" refers to preventing the occurrence of a disease and / or preventing the recurrence of a disease. DETAILED DESCRIPTION
[0030] While the present invention specification describes specific embodiments in detail, those skilled in the art should recognize that the following embodiments are illustrative and are not to be construed as limiting the present invention. Those skilled in the art will appreciate that improvements and modifications to the present invention, without departing from the principles of the present invention, will be made, and that the resulting technical solutions will fall within the scope of the claims. The following examples illustrate the beneficial effects of the present invention.
[0031] Example 1
[0032] Analysis of bladder cancer tissue transcriptome data from experimental datasets
[0033] 1. Experimental Plan The transcriptome data of 359 bladder cancer tissues (TCGA-BLCA) were analyzed.
[0034] 2. Experimental Results Figure 1 To analyze the KM survival curve of 359 bladder cancer tissue transcriptome data (TCGA-BLCA) according to CD74 expression.
[0035] Figure 2 Forest plot multivariate Cox regression analysis for CD74 expression, gender, and bladder cancer stage.
[0036] Figure 3 Methods Based on CD74 expression, 359 bladder cancer tissues were divided into two groups: CD74 high expression group and CD74 low expression group. The expressions of PDCD1 and CD274 were compared between the two groups.
[0037] Figure 4 This is a correlation analysis chart of CD74, PDCD1 and CD274 expressions.
[0038] Figure 5 The response index of anti-CTLA-4 and anti-PD-1 antibodies in the CD74 high and low expression groups.
[0039] 3. Results Analysis By analyzing the transcriptome data of 359 bladder cancer tissues (TCGA-BLCA), it was found that patients with high expression of CD74 had a better prognosis ( Figure 1 Furthermore, by performing multivariate COX regression analysis on the clinical independence of CD74 in the TCGA dataset, we found that CD74 expression was associated with survival ( Figure 2 Patients with high CD74 expression also had higher PDCD1 and CD274 expression ( Figure 3 ), CD74 expression was positively correlated with PDCD1 and CD274 expression ( Figure 4 ).
[0040] Figure 5 Further analysis of the relationship between CD74 expression and immunotherapy characteristics revealed that higher immunophenotypic scores were associated with higher response rates. Specifically, ips_ctla4_neg_pd1_neg indicates no response to either anti-CTLA-4 or anti-PD-1 antibodies; ips_ctla4_neg_pd1_pos indicates no response to anti-CTLA-4 but response to PD-1; ips_ctla4_pos_pd1_neg indicates response to anti-CTLA-4 but no response to PD-1; and ips_ctla4_pos_pd1_pos indicates response to both anti-CTLA-4 and anti-PD-1 antibodies. Therefore, patients with high CD74 expression have higher response scores to both anti-CTLA-4 and anti-PD-1 antibody treatment, suggesting that CD74 may serve as a biomarker for bladder cancer immunotherapy.
[0041] Example 2
[0042] Analysis of bladder cancer tissue transcriptome data for validation dataset
[0043] 1. Experimental Plan The transcriptome data of 478 bladder cancer tissues in the ArrayExpress database were further validated.
[0044] 2. Experimental Results Figure 6 This is the KM survival curve analysis of the transcriptome data (ArrayExpress) of 478 bladder cancer tissues in Example 2.
[0045] Figure 7 The 478 bladder cancer tissues in Example 2 were divided into two groups: CD74 high expression group and CD74 low expression group, and the expressions of PDCD1 and CD274 in the two groups were compared.
[0046] Figure 8 This is the correlation analysis among the expressions of CD74, PDCD1 and CD274 in Example 2.
[0047] 3. Results Analysis In Example 2, patients with high expression of CD74 had a better prognosis ( Figure 6 ), patients with high CD74 expression also had higher PDCD1 and CD274 expression ( Figure 7 ), CD74 expression was positively correlated with PDCD1 and CD274 expression ( Figure 8 The results of the validation dataset are highly consistent with the experimental dataset of Example 1.
[0048] Example 3
[0049] Bladder cancer subcutaneous tumor model
[0050] 1. Experimental Plan A subcutaneous bladder cancer tumor model was constructed using the control MB49 bladder cancer cell line and the CD74-knockdown MB49 bladder cancer cell line. The specific method is as follows: on day 0, 1x10^6 control MB49 bladder cancer cells and CD74-knockdown MB49 bladder cancer cells were subcutaneously injected into the right back of C57 / BL6 mice. The subcutaneous tumor size was recorded every 2 days. On the 22nd day of inoculation, the tumor was peeled off, weighed, and photographed.
[0051] 2. Experimental Results Figure 9 This is the tumor size on day 22 of inoculation of the bladder cancer subcutaneous tumor model in Example 3.
[0052] Figure 10 This is a line graph showing the changes in tumor size over time in the subcutaneous bladder cancer model in Example 3.
[0053] Figure 11 The tumor weight on the 22nd day after inoculation of the bladder cancer subcutaneous tumor model in Example 3.
[0054] 3. Results Analysis Knockdown of CD74 leads to increased growth of subcutaneous bladder cancer tumors ( Figure 9-11 ), indicating that CD74 inhibits the growth and development of bladder cancer.
[0055] In summary, the present study found that CD74 inhibits the growth and progression of bladder cancer, suggesting that CD74 may serve as a potential therapeutic target for bladder cancer. Furthermore, high CD74 expression in bladder cancer is positively correlated with PDCD1 and CD274 expression, and is associated with a better prognosis. CD74 may serve as a biomarker for bladder cancer immunotherapy.
[0056] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Anyone skilled in the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by one of ordinary skill in the art without departing from the spirit and technical principles disclosed herein are intended to be covered by the claims of the present invention.
Claims
1. Application of CD74 agonists in the preparation of drugs for the treatment of bladder cancer.
2. Application of CD74 gene as a molecular marker in the preparation of reagents for predicting the efficacy of bladder cancer immunotherapy.
3. The use according to claim 2, characterized in that The efficacy of bladder cancer immunotherapy is predicted by detecting the expression level of the CD74 gene in patient samples. The higher the expression level of the CD74 gene, the better the efficacy of bladder cancer immunotherapy.
4. The use according to claim 2, characterized in that The CD74 gene is used as a molecular marker in the preparation of a reagent for predicting the efficacy of PD-1 / PD-L1 inhibitors in treating bladder cancer.
5. The use according to claim 4, characterized in that The efficacy of PD-1 / PD-L1 inhibitors in treating bladder cancer is predicted by detecting the expression level of the CD74 gene in patient samples. The higher the expression level of the CD74 gene, the better the efficacy of PD-1 / PD-L1 inhibitors in treating bladder cancer.
6. The use according to any one of claims 2 to 5, characterized in that: The CD74 gene is a protein encoded by the CD74 gene.
7. The use according to any one of claims 4 to 6, characterized in that The PD-1 / PD-L1 inhibitors include pembrolizumab, atezolizumab, nivolumab or their biosimilars.