Pescadillo ribosomal biogenesis factor 1 as a therapeutic target in tumor immunotherapy

Abstract

High expression of pescadillo ribosomal biogenesis factor 1 (PES1) has been reported across multiple cancer types and is significantly associated with poor prognosis. Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma, demonstrating positive correlations between PES1 and programmed death-ligand 1 (PD-L1) expression (51.72% for PES1 and 58.62% for PD-L1), as well as associations with lymph node metastasis and tumor invasion depth. However, the relationship between PES1 and PD-L1 remains incompletely defined. To further address this gap, we analyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+ T cell infiltration, alongside a positive correlation with PD-L1 expression. Based on prior findings, we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms. While these pathways require experimental validation, our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.

Key Words: Pescadillo ribosomal biogenesis factor 1; Programmed death-ligand 1; Tumor immune evasion; Tumor immunotherapy; Immune evasion mechanisms

Core Tip: In gastric cancer and head and neck squamous cell carcinoma, pescadillo ribosomal biogenesis factor 1 (PES1) and programmed death-ligand 1 (PD-L1) show significant co-expression. Across multiple tumor types, elevated PES1 is linked to poor prognosis and aggressive tumor behavior. Our analysis further reveals that PES1 expression negatively correlates with CD8+ T cell infiltration and positively correlates with PD-L1 expression. These findings suggest opportunities for combination cancer immunotherapy, although the molecular basis of PES1-PD-L1 interactions and the therapeutic benefit of dual targeting require further experimental validation.

TO THE EDITOR

Pescadillo ribosomal biogenesis factor 1 (PES1) has emerged as a potential prognostic biomarker and therapeutic target across multiple malignancies, yet its role in tumor immune evasion remains unclear. Hu et al[1] recently reported significant co-expression of PES1 and programmed death-ligand 1 (PD-L1) in gastric cancer (GC) and head and neck squamous cell carcinoma (HNSCC), with correlations to adverse clinical features. While their study was limited by methodological constraints, its findings nevertheless provide important insights into immune evasion mechanisms. To further explore this relationship, we analyzed GC data from The Cancer Genome Atlas (TCGA, namely the gastric adenocarcinoma dataset) and observed a negative correlation between PES1 expression and CD8+ T cell infiltration, alongside a positive correlation with PD-L1 expression. These findings suggest functional interactions between PES1 and PD-L1 within the tumor microenvironment. We hypothesize that PES1 may regulate PD-L1 expression through phosphatidylinositol 3-kinase/protein kinase B signaling or cellular Myc-mediated mechanisms. Although these pathways require mechanistic validation, our results highlight PES1 as a potential driver of immune evasion. Future studies should investigate the molecular basis of PES1-PD-L1 interactions and evaluate the therapeutic efficacy of dual targeting in relevant cancer models.

MAIN FINDINGS AND LIMITATIONS OF THE STUDY

Hu et al[1] reported significant positive expression rates of PES1 (51.72%) and PD-L1 (58.62%) in GC and HNSCC. PES1 expression correlated with tumor-node-metastasis stage, lymph node metastasis, and depth of infiltration (P < 0.05), while PD-L1 expression correlated with tumor differentiation, lymph node metastasis, and infiltration depth (P < 0.05). These findings suggest that PES1 and PD-L1 may contribute to tumor progression and immune evasion. However, the study was limited by substantial methodological and analytical shortcomings.

Study design limitations

The investigation enrolled only 58 patients, an insufficient sample size for a study spanning two distinct tumor entities. Case numbers for GC vs HNSCC were not reported, and the rationale for combining these biologically and clinically disparate tumor types remains unjustified. More critically, the absence of normal tissue controls or benign comparators prevents confirmation that PES1 and PD-L1 expression is truly tumor-specific. Additionally, because PES1 is a core ribosomal biogenesis factor broadly expressed in proliferating cells, the lack of analysis of other proliferation markers or related ribosomal genes represents a key oversight that limits interpretation of its biological significance.

Methodological deficiencies

The report of this study did not define the explicit criteria used for PES1 and PD-L1 positivity and omitted the scoring systems used, as well as the thresholds for staining intensity and the percentage of positive cells. Critical quality control measures were also lacking, such as the inclusion of positive and negative controls, blinded evaluation protocols, and inter-observer concordance assessments to reduce subjective bias. Although the authors stated that they used “highly specific and sensitive” monoclonal antibodies, key technical details, including antibody sources, clone designations, and working concentrations, were not reported. These omissions represent major methodological shortcomings that undermine the reproducibility and reliability of the findings.

Statistical analysis concerns

The study’s statistical approach contained several major flaws. Analyses were restricted to univariate methods and did not adjust for potential confounders such as tumor stage, grade, immune infiltration profiles, mutational burden, established PD-L1 regulators, patient demographics, or clinical characteristics. Multiple P value tests were performed without correction for multiple comparisons, which increased the likelihood of false-positive findings. In addition, the absence of a validation cohort, along with the missing effect sizes, confidence intervals, and model fit statistics, prevented assessment of the robustness or clinical relevance of the reported associations. Crucially, no follow-up data, survival outcomes, nor treatment response information were provided, which limited the evaluation of both prognostic value and translational utility of PES1 and PD-L1. In conclusion, the observed PES1-PD-L1 association may simply reflect general tumor aggressiveness or proliferative capacity rather than a specific immune evasion mechanism. The study’s conclusions therefore risk overinterpretation of limited observational data.

PES1 AS AN ONCOGENIC DRIVER: MULTIFACETED MECHANISMS IN TUMORIGENESIS

PES1 is a highly conserved nucleolar protein essential for ribosome biogenesis, particularly in precursor rRNA processing and 60S ribosomal subunit assembly. As a core component of the PeBoW complex (composed of PES1, block of proliferation 1, and WD repeat domain 12), it coordinates ribosomal processing events that are indispensable for cellular proliferation[2]. Beyond its role in ribosome assembly, PES1 contributes to telomere homeostasis through formation of the PES1-telomerase reverse transcriptase-telomerase RNA complex with telomerase reverse transcriptase and telomerase RNA, thereby maintaining telomere integrity and delaying replicative senescence[3].

Overexpression of PES1 has been documented in multiple malignancies, including hepatocellular carcinoma[4], thyroid cancer[5], colorectal cancer[6], breast cancer[7], esophageal squamous cell carcinoma[8], and pancreatic cancer[9]. In these cancers, elevated PES1 Levels are strongly associated with poor prognosis and aggressive tumor behavior. Mechanistically, PES1 promotes tumorigenesis through modulation of oncogenic signaling pathways: In hepatocellular carcinoma, it activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling[4]; in breast cancer, it regulates the estrogen receptor alpha/estrogen receptor beta balance[7]; and in pancreatic cancer, it drives proliferation via cellular-Myc upregulation[9]. Collectively, these diverse functions underscore PES1 as a critical oncogenic driver and a promising therapeutic target.

ROLE OF PES1 IN CANCER IMMUNOTHERAPY: MECHANISTIC INSIGHTS INTO ITS INTERACTION WITH PD-L1

Research has shown that PES1 disrupts interleukin-enhancer binding factor 3-interleukin 15 complex formation in esophageal squamous cell carcinoma, thereby suppressing CD8+ T cell infiltration[8]. Although Hu et al[1] suggested a link between PES1 and tumor immunity in GC and HNSCC, the supporting evidence remains limited. To further evaluate this relationship in GC, we analyzed data from TCGA and observed a significant negative correlation between PES1 expression and CD8+ T cell infiltration (P = 1.29 × 10^-3) (Figure 1A). These findings indicate that high PES1 expression is associated with reduced cytotoxic T lymphocyte presence in the tumor microenvironment, potentially facilitating immune evasion[10]. Consistent with the observations by Hu et al[1], however, we also detected a significant positive correlation between PES1 and PD-L1 expression in the TCGA cohort (P = 6.12 × 10^-5) (Figure 1B). This suggests that PES1 and PD-L1 may act synergistically to promote immune evasion.

Figure 1 Correlation analysis of pescadillo ribosomal biogenesis factor 1 expression with immune markers in gastric cancer from The Cancer Genome Atlas database. A: Scatter plot showing the correlation between pescadillo ribosomal biogenesis factor 1 expression (log2-transformed) and CD8+ T cell infiltration levels in gastric cancer tissues; B: Scatter plot demonstrating the correlation between programmed death-ligand 1 expression and pescadillo ribosomal biogenesis factor 1 expression in gastric cancer samples. PES1: Pescadillo ribosomal biogenesis factor 1.

To investigate potential mechanisms linking PES1 and PD-L1, we conducted a comprehensive literature review. Prior studies have shown that PES1 promotes phosphatase and tensin homolog phosphorylation, leading to conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol (3,4,5)-trisphosphate, subsequent 3-phosphoinositide dependent protein kinase-1 activation, and AKT phosphorylation[4]. Activation of the PI3K/AKT pathway is well established as a driver of PD-L1 upregulation across diverse tumor types. Specifically, PI3K/AKT signaling activates mammalian target of rapamycin[11], which enhances PD-L1 mRNA translational efficiency[12]. The mechanistic target of rapamycin complex 1 phosphorylates S6 kinase 1 and inactivates 4E-binding protein 1, thereby promoting PD-L1 translation via the S6 kinase 1-initiation factor 4E axis[13,14]. In addition, PI3K/AKT signaling can increase PD-L1 through transcription 3 phosphorylation[15] and hypoxia-inducible factor-1 alpha stabilization[12,16]. Beyond PI3K/AKT, PES1 also modulates PD-L1 indirectly through cellular-Myc. Acetylated PES1 is recognized by bromodomain-containing protein 4 (BRD4), forming a PES1-BRD4 complex that binds the cellular-Myc promoter and enhances cellular-Myc transcription[9]. Elevated cellular-Myc, in turn, directly binds to the PD-L1 promoter region, increasing PD-L1 mRNA and protein expression[17].

Based on these findings, we propose that PES1 may regulate PD-L1 expression via two complementary mechanisms: Modulation of the PI3K/AKT signaling pathway, and the PES1-BRD4-cellular-Myc axis (Figure 2). It is important to emphasize that these hypotheses are currently theoretical, derived from the published literature, and require rigorous functional and mechanistic validation. Moreover, the regulatory relationship between PES1 and PD-L1 may vary across tumor types, underscoring the need to investigate this mechanism in multiple cancer models to assess its generalizability.

Figure 2 Proposed molecular mechanisms underlying pescadillo ribosomal biogenesis factor 1-mediated regulation of programmed death-ligand 1 expression and tumor immune evasion. Created with Figdraw.com. PD-L1: Programmed death-ligand 1; PES1: Pescadillo ribosomal biogenesis factor 1; PD-1: Programmed cell death protein 1; mTORC: Mechanistic target of rapamycin complex; AKT: Protein kinase B; PDK1: 3-phosphoinositide dependent protein kinase-1; PIP2: Phosphatidylinositol 4,5-bisphosphate; PIP3: Phosphatidylinositol (3,4,5)-trisphosphate; PTEN: Phosphatase and tensin homolog; BRD4: Bromodomain-containing protein 4; c-Myc: Myelocytomatosis oncogene.

CONCLUSION

Elevated PES1 expression is associated with poor prognosis and aggressive tumor behavior across multiple malignancies. However, the study by Hu et al[1] examining PES1 and PD-L1 co-expression in GC and HNSCC had substantial methodological limitations. Our analysis of TCGA data revealed a negative correlation between PES1 expression and CD8+ T cell infiltration, alongside a positive correlation with PD-L1 expression. Based on prior research, we further hypothesize that PES1 may regulate PD-L1 via the PI3K/AKT signaling pathway or the cellular-Myc-mediated axis. These observations provide novel insights into tumor immune evasion and establish a theoretical foundation for PES1-targeted therapeutic strategies. Future studies should aim to validate these regulatory mechanisms and evaluate the clinical potential of PES1 as a target in cancer immunotherapy.