WCLC 2025 - Posters & ePosters-P2.06.28 GPC3 Upregulation After Neoadjuvant Chemoimmunotherapy Associates With Adverse Outcomes and Tumor Heterogeneity in Squamous NSCLC

P2.06.28 GPC3 Upregulation After Neoadjuvant Chemoimmunotherapy Associates With Adverse Outcomes and Tumor Heterogeneity in Squamous NSCLC

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This study investigates the role of Glypican-3 (GPC3) expression in lung squamous cell carcinoma (LUSC) patients undergoing neoadjuvant immunochemotherapy. LUSC accounts for 20-30% of non-small cell lung cancer (NSCLC), and neoadjuvant immunochemotherapy has become standard treatment for resectable cases. However, existing evaluation methods like major pathological response have limited predictive value for long-term outcomes. GPC3, known as a prognostic marker in hepatocellular carcinoma, had an unclear role in LUSC tumor microenvironment (TME) remodeling and therapy-induced changes prior to this study.<br /><br />The study enrolled 68 LUSC patients—24 undergoing direct surgery without neoadjuvant therapy and 44 receiving neoadjuvant immunochemotherapy followed by surgery—and 15 patients with bone metastases. GPC3 expression was assessed via immunohistochemistry. Results showed a higher proportion of GPC3-positive tumors in the neoadjuvant group (73%) compared to direct surgery patients (54%), with significantly elevated GPC3-positive cell proportions post-neoadjuvant therapy (median 50% vs. 15%, p=0.013). Conversely, only 13% of bone metastases were GPC3-positive, significantly lower than primary lung lesions (p=0.017). This suggests neoadjuvant immunochemotherapy induces GPC3 upregulation in primary tumors but not metastases, implying tumor heterogeneity and potential epigenetic changes during metastatic progression.<br /><br />Clinically, GPC3 positivity strongly correlated with early postoperative recurrence: 75% of GPC3-positive patients relapsed versus 9.1% of GPC3-negative (p=0.00056). Event-free survival was significantly shorter in the GPC3-positive group (median 17.7 months) compared to negatives, confirmed by Kaplan-Meier analysis (p=0.0117). Adjuvant therapy did not affect recurrence risk, underscoring GPC3’s prognostic value.<br /><br />The study is the first to link neoadjuvant immunochemotherapy-induced GPC3 upregulation with adverse outcomes and tumor heterogeneity in LUSC. Limitations include a modest sample size (n=83) and lack of multi-omics validation. The authors recommend future studies employing single-cell RNA sequencing and spatial transcriptomics to clarify GPC3’s functional role in LUSC progression and therapy response.

Asset Subtitle

Linqiang Jiang

Meta Tag

Speaker Linqiang Jiang

Topic Pathology and Biomarkers

Keywords

Glypican-3

GPC3 expression

lung squamous cell carcinoma

LUSC

neoadjuvant immunochemotherapy

tumor microenvironment remodeling

tumor heterogeneity

early postoperative recurrence

prognostic marker

non-small cell lung cancer