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Infiltration of tumor-associated macrophages and its association with prognosis of patients with diffuse large B-cell lymphoma based on gene expression profile data / 白血病·淋巴瘤
Journal of Leukemia & Lymphoma ; (12): 143-150, 2022.
Article in Chinese | WPRIM | ID: wpr-929749
ABSTRACT

Objective:

To analyze the infiltration of tumor-associated macrophages and their subtypes, and to investigate their association with prognosis of patients with diffuse large B-cell lymphoma (DLBCL) based on the gene chip expression database.

Methods:

The data were retrieved from microarray (Affymetrix U133 plus 2.0) database (NoGSE10846) of DLBCL patients in PubMed gene expression omnibus (GEO). The database included 414 DLBCL patients, among which 306 cases had complete clinical, cell of origin phenotype (COO subtyping), treatment and follow-up information. The data analysis was performed on the online computer program which could identify the cell-type (CIBERSORT) by estimating relative percentage of RNA transcripts. From the returned result file, the percentage of immune cells including macrophages subtypes of all cases in all identifiable immune cells in the microenvironment was identified in GSE10846 database. Taking the median percentage of macrophages subsets in all types of immune cells as cut-off value; ≥ cut-off value was high infiltration and < cut-off value was low infiltration. The median value of gene RNA expression level of myc, bcl-2, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2) of 414 DLBCL patients in the GSE10846 database was treated as the cut-off value; ≥ cut-off value was the high expression and < cut-off value was the low expression. The correlation of the expression levels of all subsets and total macrophages with clinical factors, gene expression, survival was analyzed; Cox proportional hazard model was used to make multivariate analysis of the prognosis for DLBCL patients. surv_cutpoint function of surv_miner package in R 4.0.4 software was used for the optimal cut-off value of the percentage of macrophages subsets in all immune cells in the microenvironment; the result less than the optimal cut-off value was statistically low infiltration and the result greater than or equal to the optimal cut-off value was statistically high infiltration.

Results:

CIBERSORT analysis showed that M0 macrophages [15.00% (0-44.41%)], M1 macrophages [7.46% (0-23.00%)] and M2 macrophages [6.28% (0-43.35%)] in the tumor microenvironment were identified in all 414 DLBCL cases. Among 306 patients with complete clinical and follow-up data, there were 155 cases (50.7%), 152 cases (49.7%), 156 cases (51.0%), 152 cases (49.7%), respectively in high infiltration patients with M0, M1, M2 and total macrophages; the high infiltration of M0 macrophages was correlated with COO subtyping germinal center B-cell (GCB) type and the high expression of PD-L1 gene, the absence of myc and bcl-2 double high expression at RNA level (R-DEL) (all P < 0.05); the high infiltration of M1 macrophages was correlated with female, the high expression of PD-L1 gene and PD-L2 gene (all P < 0.05); the high infiltration of M2 macrophages was correlated with COO subtyping GCB type, the high expression of PD-L2 gene (all P < 0.05); the high infiltration of total macrophages was correlated with female, COO subtyping GCB type, the high expression of PD-L1 gene and PD-L2 gene, the absence of R-DEL (all P < 0.05).The high expression of PD-L1 gene was associated with high infiltration of M0, M1 and total macrophages (all P < 0.01), and high PD-L2 gene expression was correlated with high infiltration of M1, M2 and total macrophages (all P < 0.01). The overall survival (OS) of M0 macrophage high infiltration group was better than that of the lower infiltration group ( P = 0.002); the OS of M2 macrophage low infiltration group was better than that of the high infiltration group ( P = 0.019). The OS of R-DEL group was worse than that of R-DEL absent group ( P = 0.001). The patients with low international prognostic index (IPI) score (0-2), COO subtyping GCB type, and treatment with rituximab had better OS (all P < 0.01). Multivariate Cox regression analysis showed that 60 years or above, COO subtyping non-GCB type, treatment without rituximab, M0 macrophage low infiltration, M2 macrophage high infiltration were all independent adverse prognostic factors for OS of DLBCL patients (all P < 0.05). The optimal cut-off value for M0 macrophages was 4.3%, and the optimal cut-off value for M2 macrophages was 4.8%, and the OS in the group with statistically low infiltration of M0 macrophage was worse ( P < 0.001), and so was the OS in the group with statistically high infiltration of M2 macrophage ( P = 0.001).

Conclusions:

Tumor-associated macrophage is confirmed as the most abundant immune cells in the tumor microenvironment of DLBCL. Patients with high infiltration of M2 macrophage have poor prognosis, while high infiltration of M0 macrophage indicates a better prognosis.

Full text: Available Index: WPRIM (Western Pacific) Type of study: Prognostic study Language: Chinese Journal: Journal of Leukemia & Lymphoma Year: 2022 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Type of study: Prognostic study Language: Chinese Journal: Journal of Leukemia & Lymphoma Year: 2022 Type: Article