SUMMARY: Pregnancy-Specific Glycoproteins (PSGs), traditionally known for their role in fetal development and maternal immune tolerance, are emerging as unexpected contributors to oncologic processes. These placental proteins, members of the CarcinoEmbryonic Antigen Cell Adhesion Molecule (CEACAM) family and the broader immunoglobulin superfamily, are produced by trophoblasts and secreted into maternal circulation during pregnancy in high concentrations and act as immunomodulators, facilitating maternal-fetal tolerance and vascular remodeling. However, recent evidence suggests that these proteins may be aberrantly expressed in several malignancies, including lung cancer, with potentially detrimental effects, particularly among female patients.
Background and Rationale
While PSGs are primarily restricted to the placenta under normal physiological conditions, prior research has revealed their ectopic expression in various cancers such as breast, ovarian, uterine, and colon tumors. Their expression in these settings has been correlated with poorer overall survival. Yet the mechanisms and potential sex-specific effects remained unclear. Recognizing the immunological parallels between pregnancy and tumor immune evasion, researchers hypothesized that PSGs might confer a selective disadvantage in cancers by modulating the tumor microenvironment in a sex-dependent manner.
Study Design and Methodology
To explore this hypothesis, investigators conducted a sex-stratified analysis of PSG expression and survival outcomes using two independent transcriptomic datasets: The Cancer Genome Atlas (TCGA), encompassing 235 male and 271 female Lung Adenocarcinoma patients, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), including 70 male and 36 female patients. PSG mRNA expression profiles were integrated into machine learning models to assess their prognostic value. Key PSG family members, PSG3, PSG7, and PSG8 were specifically examined for their association with survival outcomes.
Key Findings
This analysis revealed a striking sex-specific prognostic disparity in Lung Adenocarcinoma. Female patients with elevated PSG expression exhibited significantly worse Overall Survival compared to their PSG-negative counterparts, a trend not observed in male patients. Notably, a combined expression signature of PSG3, PSG7, and PSG8 identified a high-risk subgroup encompassing approximately 30% of female patients. This signature was significantly associated with poor prognosis.
Pathway enrichment analysis further uncovered that PSG-expressing female Lung Adenocarcinoma tumors showed upregulation of the “KRAS Signaling Down” pathway, suggesting a potential mechanistic link. Incorporating KRAS pathway activity into the predictive model improved its prognostic performance in female patients, reinforcing the notion that PSGs may interface with oncogenic KRAS signaling in a sex-dependent fashion.
Clinical Implications
These findings underscore a previously unrecognized, sex-specific role for PSGs in modulating lung cancer outcomes. The ectopic expression of PSGs appears to mimic their immune-regulatory function during pregnancy, potentially allowing tumors to evade immune surveillance, particularly in female patients. As a result, PSG expression may serve as a prognostic biomarker and a novel therapeutic target in Lung Adenocarcinoma.
The research team is now investigating the development of antibody-based therapeutics aimed at inhibiting PSG expression, with the goal of improving outcomes in this vulnerable subgroup of female Lung Adenocarcinoma patients. Given that PSGs are typically silenced outside of pregnancy, targeting them may provide a tumor-specific strategy with minimal off-target effects.
Future Directions
Further investigations are planned to delineate the interplay between PSG expression, pregnancy history, and hormone-related gene activity. Such studies could elucidate whether reproductive history or endocrine factors influence the reactivation of PSG genes in female tumors, potentially refining risk stratification and therapeutic approaches.
Conclusion
This research highlights the adaptive reuse of fetal tolerance mechanisms by tumors and reveals PSGs as key contributors to sex-specific disparities in Lung Adenocarcinoma prognosis. By integrating transcriptomic profiling with clinical outcomes and pathway analysis, this study provides a compelling rationale for the clinical development of PSG-targeted therapies in female Lung Adenocarcinoma.
Pregnancy-specific glycoproteins in tumors are strong predictors of outcome in female lung adenocarcinoma patients. Oh JH, Rizzuto G, Elkin R, et al. Presented on April 28, 2025: AACR Annual Meeting 2025.
