Lung Cancer Hijacks Pregnancy-Specific Genes to Evade Immune Surveillance, Leading to Worse Outcomes in Women
In a groundbreaking study from Memorial Sloan Kettering Cancer Center (MSK), researchers have uncovered a sinister mechanism by which lung cancer exploits genes typically reserved for fetal development to sabotage the body’s immune defenses. These pregnancy-specific glycoproteins (PSGs), essential for protecting a fetus from maternal immune attack, become aberrantly activated in tumors, conferring a survival advantage to cancer cells. Strikingly, this activation correlates with significantly poorer clinical outcomes in female lung cancer patients compared to their male counterparts, illuminating a crucial sex-based disparity in lung adenocarcinoma prognosis.
PSGs are a family of glycoproteins abundantly produced by the placenta during gestation, orchestrating an immunotolerant environment that shields the fetus. By modulating the maternal immune system, PSGs prevent rejection of the semiallogeneic fetus, ensuring successful pregnancy. Intriguingly, prior investigations at MSK first revealed that around 20% of various malignancies, including lung, breast, uterine, and colon cancers, aberrantly express PSG genes, raising the hypothesis that tumors may co-opt these immunomodulatory proteins to evade immune detection and destruction.
Building on this foundation, the current study delves into the sex-specific implications of PSG activation in lung cancer, employing cutting-edge computational modeling and machine learning techniques. Led by Joseph Deasy, PhD, Chair of MSK’s Department of Medical Physics, and first author Jung Hun Oh, PhD, the team analyzed RNA sequencing datasets from over 500 lung cancer patients, integrating transcriptomic profiles with clinical survival data. Their rigorous bioinformatic assessment uncovered that female patients whose tumors express PSGs endure substantially worse survival probabilities than males with comparable gene expression patterns.
Further mechanistic insights emerged when the researchers observed a consistent association between PSG expression and dysregulation of the KRAS signaling pathway in female patients. The KRAS oncogene encodes a critical molecular switch regulating cell proliferation and survival, and its mutations are a hallmark of many cancers, including lung adenocarcinoma. The dual presence of PSG activation and KRAS pathway perturbation suggests a synergistic effect driving aggressive tumor behavior and resistance to conventional therapies. Conversely, male patients exhibiting PSG expression did not experience comparable survival detriment, underscoring a profound sex-specific biological divergence.
To validate their findings, the group utilized two complementary RNA-Seq datasets: the extensive The Cancer Genome Atlas (TCGA) compendium comprising 235 males and 271 females, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) cohort with 70 males and 36 females. Notably, the CPTAC cohort, enriched with proteomic data, confirmed and even amplified the survival disparities observed, affirming the robustness of the PSG-driven prognostic effect in female lung cancer patients. This independent replication bolsters confidence in PSGs as critical mediators of sex-specific tumor evolution.
The implications of these findings are profound. Whereas current therapeutic strategies largely overlook sex-based biological differences, particularly at the molecular and immunological interfaces, this research shines a spotlight on the necessity of personalized approaches tailoring treatments based on PSG expression status and sex. The aberrant activation of pregnancy-related glycoproteins in tumors unveils a novel immune escape axis that might be exploited therapeutically, especially since PSGs exhibit highly restricted expression outside pregnancy, minimizing off-target effects.
Intriguingly, the team also contemplates deeper hormonal and reproductive factors that might modulate PSG induction and KRAS pathway interactions. Female patients’ pregnancy history, endogenous hormone levels, and hormone-responsive gene networks may intersect with this mechanism, representing fertile ground for future investigation. Deciphering these complex layers holds promise not only for lung cancer but potentially for other malignancies harboring PSG expression.
Molecular targeting of PSGs or the downstream signaling cascades they influence could redefine the treatment landscape. Given the apparent absence of PSG expression in normal adult tissues beyond pregnancy, drugs aiming to inhibit PSG-related pathways might achieve high tumor specificity with manageable toxicity profiles. This transformative avenue might be especially critical for female lung cancer patients—long recognized as bearing distinct clinical features but underserved by sex-specific regimens.
This innovative research was made possible through interdisciplinary collaboration between medical physics, oncology, computer science, and immunology experts at MSK, with contributions from outside institutions including the Uniformed Services University of Health Sciences. The study received vital funding from the National Cancer Institute and Breast Cancer Research Foundation, underscoring the importance of sustained investment in cancer research focusing on biological sex differences.
As cancer biology delves ever deeper into the intricate interplay between genetics, sex, and the immune system, the discovery that tumors can mimic fetal immune protection mechanisms reveals a new frontier in understanding malignancy and therapy resistance. This insight challenges prevailing dogma and calls for integrative strategies bridging developmental biology and oncology.
In concluding remarks, Dr. Joseph Deasy emphasized the translational potential of targeting PSG-related pathways to improve outcomes in female lung cancer patients. “Our findings reveal PSGs as promising, tumor-specific biomarkers and drug targets,” he states, “that could enable more precise, efficacious interventions. This approach exemplifies precision medicine’s promise, harnessing deep molecular insights to tackle the complex heterogeneity of cancer.” With such promising avenues unfolding, the landscape of lung cancer therapeutics is poised for paradigm-shifting innovation.
Subject of Research: Pregnancy-specific glycoproteins (PSGs) expression in lung cancer and their sex-specific impact on patient outcomes
Article Title: Pregnancy-specific glycoproteins in tumors are strong predictors of outcome in female lung adenocarcinoma patients
News Publication Date: AACR Annual Meeting 2025
Web References:
- Memorial Sloan Kettering Lung Cancer Research Profiles
- The Cancer Genome Atlas (TCGA)
- Clinical Proteomic Tumor Analysis Consortium (CPTAC)
- AACR Annual Meeting Abstract Archive
References:
- Prior MSK publication on PSG gene activation in cancers (PNAS)
- AACR 2025 presentation on PSGs and lung cancer sex differences
Image Credits: Memorial Sloan Kettering Cancer Center
Keywords: Lung cancer, pregnancy-specific glycoproteins, PSG, KRAS pathway, sex differences, immunomodulation, AI/machine learning, tumor immunology, personalized medicine, biomarker, lung adenocarcinoma, cancer research
