Introduction
Ovarian cancer (OC) is one of the most prominent and potentially lethal gynecological malignancies, with a reported 313,959 newly diagnosed cases and 207,252 fatalities globally in 2020 [
1]. Due to the lack of a mechanism for early detection and specific early-warning symptoms, OC patients are often diagnosed at an advanced stage, resulting in a 5-year survival rate of only 47% [
2]. Although conventional platinum-based chemotherapeutic agents and cytoreductive resection can achieve complete remission, the majority of patients will eventually develop treatment resistance [
3]. Immunotherapy has made significant advances in the last two decades and has ushered in a new era in the treatment of various cancers [
4]. Although the success rate of OC immunotherapy remains unsatisfactory, the use of immune-checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR), and T cell receptor-engineered T cells is advancing rapidly [
5].
The tumor microenvironment (TME) has recently been found to have an instrumental function in the carcinogenesis of OC [
6]. A specialized subset of fibroblasts called cancer-associated fibroblasts (CAFs) performs a critical function in the microenvironment of solid tumors, where they can modulate cancer progression and metastasis [
7]. It has been demonstrated that CAFs can promote cancer progression by secreting growth factors, cytokines, and chemokines, and by degrading the extracellular matrix (ECM) [
8‐
10]. CAFs have also been shown to generate prometastatic cytokines in a paracrine manner, thereby facilitating the metastasis of OC cells [
11]. Moreover, CAFs contribute to immune evasion by upregulating of immune checkpoint ligands and immunosuppressive cytokines, hindering the infiltration of anti-tumor CD8 + T lymphocytes and provoking an anti-tumor response through interaction with other immune cells [
12]. Increasing evidence suggests that CAFs mediate chemoresistance in OC [
13]. Therefore, CAFs represent a promising therapeutic target for the treatment of OC [
14].
The study aimed to fill a gap in our understanding of the role of CAFs in OC and to investigate their potential as a prognostic biomarker and therapeutic target. By analyzing scRNA-seq and transcriptomic data, the researchers could identify CAFs subclusters and develop a risk signature that was predictive of prognosis in OC patients. They also explored the relationship between the risk signature and the immune landscape of the tumor microenvironment and found that it was predictive of response to immunotherapy. Finally, the researchers developed a nomogram that integrated the CAF-based signature with other variables to aid in predicting the prognosis of OC patients in clinical settings.
Discussion
CAFs play a critical role in promoting the growth of OC cells by inducing tumor cell proliferation, angiogenesis, and immune suppression [
26]. Studies have shown that CAF-secreted IL-8 can enhance OC stemness and malignancy, while exosomes from omental CAFs can increase peritoneal metastasis [
27]. The gene GLIS1, which is upregulated in metastatic CAFs, can also promote OC cell migration and invasion [
28]. However, much is still to be learned about the role of CAF-related genes in OC, and many researchers have focused on the impact of single genes. By studying gene signatures associated with CAFs, it may be possible to better understand the mechanisms behind OC progression and develop more targeted treatment strategies.
In this work, we analyzed the diversity of CAFs and conducted a comprehensive characterization and categorization of CAFs of OC using scRNA-seq data. The TME was divided into five CAFs clusters, each of which had unique characteristics and may have helped regulate some aspect of TME biology. A growing body of research has established the predictive significance of a CAF-associated gene signature in OC. Our findings showed that a score calculated from DEGs for the five clusters consistently illustrated that two clusters strongly correlate with the prognosis of OC individuals. Furthermore, CAF’s predictive performance could be attributed to the variations in WNT and NOTCH pathways we observed across CAFs groups. OC onset and progression may be enhanced by inhibiting apoptosis and promoting cell proliferation and differentiation via the stimulation of the WNT signaling pathway [
29]. Additionally, The Notch signaling pathway is proven as a prominent component of OC implicated in the proliferation, migration, invasion, and treatment resistance [
30].
Numerous studies have demonstrated that increased CAFs can act as an unfavorable prognostic factor in OC patients. Within the context of fibroblast biology and the tumor microenvironment in OC, CAFs, a group of non-immune-related tumor cells, may actively contribute to the proliferative, migratory, and metastatic capacities of tumor cells. Based on the high predictive value of two CAFs clusters, we have developed a CAF-based risk signature comprising seven genes. Of note, one of these genes, CXCL9, which acts as a ligand of CXCR3, has been reported to have a controversial role in tumor initiation and progression, exhibiting both positive and negative prognostic values depending on the type of tumor [
31]. Interestingly, patients with OC who display elevated levels of CXCL9 have shown significantly higher relapse-free survival rates than those with low levels [
32]. In response to Ras signaling, the transcriptional inhibitor ELK3 is transformed into a transcriptional activator by the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) [
33]. ELK3 overexpression has been observed in both OC cell lines and human malignancies [
34]. CACNA1C, which encodes the alpha-1 subunit of a voltage-dependent calcium channel, has been linked to the modulation of cell adhesion, collagen fibril organization, cell-matrix adhesion, cell response to amino acid stimulation, and negative control of cell proliferation [
35]. Previous research has shown a significant decrease in CACNA1C expression levels in OC tissues compared to healthy tissues [
36]. The Golgi enzyme MAN2A1 is essential for transforming high mannose into a complex N-glycan structure to complete the glycosylation of protein membranes [
37]. When fused with FER, MAN2A1 transforms into an oncogene; around 80% of prostate cancer patients with MAN2A1-FER have exhibited a dismal clinical prognosis according to earlier studies [
38]. VSIG4, a novel macrophage protein linked to the B7 family, can inhibit T cell activation and may be involved in the onset and progression of cancer [
39]. By suppressing the activity of complement pathways or T cells and promoting the development of regulatory T cells, VSIG4 can maintain immune system homeostasis, thereby inhibiting the progression of immune-induced inflammatory diseases but promoting cancer advancement [
40]. However, there is a scarcity of functional validation for the seven genes implicated in the CAFs of OC, necessitating further investigations of the 7 CAFs markers.
New research indicates that CAFs may enhance tumor development through their interactions with the TME [
41]. Our analysis revealed that six the prediction genes positively correlated with the immune score. In contrast, while one risk gene had a negative correlation, suggesting possible interactions between these genes and the TME in OC. This highlights the potential of these genes as treatment targets for OC. The TME comprises various immune cells that work together to create an anti-tumor immune response. CAFs can create an immunosuppressive TME that helps cancer cells evade immune surveillance by interacting with immune cells. Our research showed that the prognostic genes of the risk signature were positively correlated with many types of T cells, which play a critical role in tumor growth and are promising targets for immunotherapies such as ICI and CAR-T cell therapy [
42]. The risk signature may also identify patients most likely to respond to immunotherapies.
Furthermore, the results demonstrated that a CAFs-based signature might predict a patient’s response to anti-PD-L1 immunotherapy. Our findings provide valuable insights into CAFs’ role in reshaping the cancer niche and immune state in TME. Nevertheless, further studies are warranted to clarify the significance of CAFs-TME crosstalk in OC and its potential for use in OC immunotherapy.
However, it is important to note that our study has several limitations. First, we utilized retrospective data from public repositories to establish the CAFs clusters and risk signature. Therefore, it will be imperative to validate its effectiveness in additional prospective and multicenter studies involving OC patients in the future. Second, the CAF-based risk signature was only assessed for its potential prognostic value; further investigation is needed to elucidate the underlying mechanisms by which this signature contributes to the initiation and progression of OC.
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