Abstract
Diffuse large B-cell lymphoma (DLBCL) is an extremely heterogeneous tumor entity, which makes prognostic prediction challenging. The tumor microenvironment (TME) has a crucial role in fostering and restraining tumor development. Consequently, we performed a systematic investigation of the TME and genetic factors associated with DLBCL to identify prognostic biomarkers for DLBCL. Data for a total of 1,084 DLBCL patients from the Gene Expression Omnibus database were included in this study, and patients were divided into a training group, an internal validation group, and two external validation groups. We calculated the abundance of immune–stromal components of DLBCL and found that they were related to tumor prognosis and progression. Then, differentially expressed genes were obtained based on immune and stromal scores, and prognostic TME‐related genes were further identified using a protein–protein interaction network and univariate Cox regression analysis. These genes were analyzed by the least absolute shrinkage and selection operator Cox regression model to establish a seven-gene signature, comprising TIMP2, QKI, LCP2, LAMP2, ITGAM, CSF3R, and AAK1. The signature was shown to have critical prognostic value in the training and validation sets and was also confirmed to be an independent prognostic factor. Subgroup analysis also indicated the robust prognostic ability of the signature. A nomogram integrating the seven-gene signature and components of the International Prognostic Index was shown to have value for prognostic prediction. Gene set enrichment analysis between risk groups demonstrated that immune-related pathways were enriched in the low-risk group. In conclusion, a novel and reliable TME relevant gene signature was proposed and shown to be capable of predicting the survival of DLBCL patients at high risk of poor survival.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous tumor entity with a striking degree of genetic and clinical heterogeneity
The results demonstrated that low-risk patients had significantly favorable overall survival (OS) compared to high-risk patients with the activated B-cell-like (ABC) subtype of DLBCL (p = 0.0014; HR = 2.04; 95% confidence interval (CI) = 1.31–3.19; Figure 5A)
To evaluate whether the risk prediction model could be used as an independent prognostic index for DLBCL patients, analyses were performed to identify the factors affecting the prognosis of DLBCL patients. These analyses were performed only on the datasets that included clinical International Prognostic Index (IPI) components data (GSE31312 and GSE10846), and the results showed that the seven-gene signature was an independent prognostic factor in these datasets (Table 2)
Summary
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous tumor entity with a striking degree of genetic and clinical heterogeneity. The heterogeneity of the tumor, in particular, poses a major barrier to understanding the genetic basis of the disease and its response to therapy [3]. A better understanding of the interactions between the TME and the immune response may provide new approaches to improve the efficiency of current immunotherapies, especially immune checkpoint inhibitor and chimeric antigen receptor (CAR) T cell therapies [8]. Several studies have considered the latent role of the TME in the occurrence and development of DLBCL, but their results were controversial [9]
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