1 Introduction
Prostate adenocarcinoma (PRAD) remains the leading cause of cancer related mortality among men in the United States [
1]. Despite advances in clinical care, mortality rates remain high, indicating a need for better understanding of the factors influencing PRAD prognosis and treatment response [
2,
3].
Recent evidence suggests that PRAD prognosis is heavily dependent on the tumor microenvironment [
4]. The tumor immune microenvironment (TIME), comprised of extracellular matrix, stromal cells, and other tumor associated cells, can modulate the tumor’s response to therapy and can influence the progression of the tumor [
5]. TIME has been reported to profoundly influence the growth and metastasis of cancer. It affects prognosis, tumor growth, and treatment response through a variety of mechanisms [
6]. The composition of the tumor microenvironment can affect prognosis by influencing the proliferation, metastasis, and drug resistance of cancer cells [
7]. Factors like the abundance of immune cells, angiogenesis (new blood vessel formation), and cytokines (types of proteins) released by the environment can either inhibit or promote the growth of cancer cells [
8]. These signals can also have a large impact on how a patient responds to treatment; for example, certain treatments may be targeted more directly at immunoprivileged environments, and certain drugs tested in preclinical trials may not reach the tumor due to an immunosuppressive microenvironment [
9]. In terms of tumor growth, TIME affect the rate of metastasis, and provide signals for cell growth, movement, and survival [
10]. TIME could also be a source of genetic mutations, which can lead to the selection of drug resistant tumor cells [
11]. Additionally, the presence of certain immune cells can influence the growth and progression of tumors [
12]. Finally, the microenvironment can also influence response to treatments. Factors like hypoxia (low oxygen) or the immune cell composition can affect the effectiveness of certain therapies [
13]. Additionally, certain signaling pathways in the microenvironment can be targeted by drugs to suppress tumor growth and improve outcomes [
14]. Overall, the tumor microenvironment is an essential component of tumor biology and can affect the prognosis, growth, and response to treatments of cancer.
In this study, we downloaded the PRAD RNA-sequencing (RNA-seq) data from the UCSC Xena database. Then, the ESTIMATE method was employed to analyze the immune and stromal scores and tumor purity of PRAD samples. In addition, we analyzed the correlation between TIME and clinical information, from which we obtained the novel TIME-related prognostic genes for PRAD.
4 Discussion
Multiple factors, stages, and genes are involved in the occurrence and development of PRAD, where TIME is an important factor. Recently, immunotherapy was the novel treatment for PRAD tumors, whereas the clinical outcome was related to the characteristics of malignant tumors, such as hormone dependence, low tumor mutation load, and immunosuppressive microenvironment. Besides, previous studies have found that TIME correlated with the prognosis of patients with PRAD [
27]. Thus, further exploration of TIME in PRAD was significant to help doctors make decisions about the treatment method and predict the prognosis for PRAD.
The results of this study revealed that the PRAD samples with high immune and stromal scores had a better prognosis, and those with high tumor purity had a worse prognosis. In addition, we collected the OS, RFS, and DFS of samples to examine the correlation in immune and stromal scores and survival time using KM curves. The results obtained were similar to the ESTIMATE results. These observations were consistent with the results of previous studies. For example, Chen et al. [
28] suggested that stromal, immune, and ESTIMATE scores closely correlated with the OS of patients with PRAD. In addition, similar results were obtained in multiple cancer types, such as breast cancer, bladder cancer, and lung adenocarcinoma, indicating that the stromal, immune, and ESTIMATE scores and tumor purity in TIME played a significant role in immunotherapy [
29‐
31]. Xiang et al. [
32] indicated that the stromal, immune, and ESTIMATE scores and tumor purity in the microenvironment were associated with TIME. Thus, our study screened TIME-related DEGs by comparing stromal scores and immune scores. Subsequently, 1229 TIME-related DEGs were screened using the limma package. GO BP results indicated the involvement of DEGs in the immune response. Immune response regulated the development of PRAD tumors, which played an important role when making decisions for immunotherapy [
33,
34]. The DEGs might be novel biomarkers for treating PRAD. In addition, KEGG results indicated that the DEGs were related to the cytokine–cytokine receptor interaction pathway. Previous studies have found that this pathway always involved some immune-related genes that are involved in different cancers, such as renal cell carcinoma and hepatocellular carcinoma [
35,
36]. This pathway might be an important factor in the immunotherapy for PRAD. Further experiments must be performed to understand the mechanism of immunotherapy in PRAD.
Previous studies have indicated that the TIME was related to the prognosis of patients with PRAD. In this study, three prognostic DEGs, namely,
METTL7B,
HOXB8, and
TREM1, were identified. The KM curves were used to evaluate the correlation between the three DEGs and patient prognosis, suggesting that patients with low expression levels of
METTL7B,
HOXB8, and
TREM1 had good OS, RFS, and DFS. The results were validated using the external cohort, which obtained the same results as TCGA dataset. Our results were similar with the previous studies that have used external cohorts to validated the prognostic value of the biomarkers in PRAD [
37‐
39]. The method further confirmed the results in this study. This novel TIME hub genes-related risk score model provides a new theoretical basis for the prognosis assessment of PRAD patients, which is expected to be further applied in the future clinical management. A prospective study of clinical cohorts recruiting PRAD patients in different stage will help validating this risk score model. The expression of
METTL7B,
HOXB8, and
TREM1 was examined each month. Then, the follow-up was performed to observe the prognosis of PRAD patients. The KM curves and survival analysis will be carried out to the correlation between risk score model and prognosis. This study is expected to be conducted for 5 years or even longer to obtain good persuasiveness.
Meanwhile, significant differences in
METTL7B,
HOXB8, and
TREM1 were found between the controls and tumor samples in both mRNA levels. The three genes might be novel TIME-related biomarkers for PRAD.
METTL7B, an alkyl thiol methyltransferase, could metabolize hydrogen sulfide (H
2S) [
40]. H
2S was found to participate in the epithelial–mesenchymal transition and tumor migration and invasion [
41]. A recent study found that the expression of
METTL7B positively correlated with immunosuppressive cells suggesting that it might play a significant role in modulating TIME [
42]. Meanwhile,
METTL7B expression was positively associated with CD4 + T cells and dendritic cells. All the results indicated that
METTL7B could be used to predict the TIME in PRAD. Moreover, Redecke et al. [
43] reported that
HOXB8 transfected in mouse bone marrow cells with unlimited proliferative capacity that could enable investigations of immune cell differentiation and function. This study found that
HOXB8 is closely correlated with CD4 + T cells. Besides, Zhao et al. [
44] pointed out that high expression levels of
TREM1 had improved the infiltration of regulatory T cells and reduced the infiltration of CD8 + T cells. Similarly, this study found that the expression of
TREM1 could regulate the TIME, including neutrophils and dendritic cells. Previous studies have suggested that CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells are associated with the impairment of proliferation, cytokine production, and migratory capacities of effector T cells [
45]. Besides, Meng et al. [
46] firstly pointed out the infiltration of immunocytes among PRAD via the CIBERSORT algorithm. This study indicated that M2 macrophages was related to gene markers, whick could predict the prognosis of PRAD patients. These results were consistent with our study that we found that
METTL7B,
HOXB8, and
TREM1 were positively correlated with M2 macrophages. Regulating the expression levels of
METTL7B,
HOXB8, and
TREM1 may have remarkable clinical applications in enhancing immunotherapy. Immunotherapy has shown good prospects in treating cancer. We will continue to focus on the genes related to tumor microenvironment of PRAD in the future. Further exploration on genes related to tumor microenvironment will help treating patients with PRAD using immunotherapy as soon. Thus, more experiments such as mice experiments, molecular biology research and clinical test need be performed to validate these results in this study.
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