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FGF/FGFR genomic amplification as a predictive biomarker for immune checkpoint blockade resistance: a short report
Nicolas Roussot1,2,3,4, Julie Lecuelle5,3,4, Lorraine Dalens2
1Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, Bourgogne-Franche-Comté, France nroussot@cgfl.fr fghiringhelli@cgfl.fr.
Abstract:
A novel crosstalk between immunogenic and oncometabolic pathways triggered by T cell-released interferon-gamma (IFN-ɣ) has been recently identified. This IFN-ɣ-pyruvate kinase M2-β-catenin axis relies on fibroblast growth factor 2 (FGF2) signaling in tumor cells and leads to hyperprogressive disease on immune checkpoint blockade (ICB) in preclinical models. This result underlines how IFN-ɣ signaling may have distinct effects on tumor cells depending on their oncogenic and metabolic features. On the basis of these data, this study aims to explore the relationship between genomic tumor FGF2 or FGF/FGF receptor (FGFR) amplification and immunotherapy response in patients with metastatic solid cancers. We used a large genomic data set of 545 ICB-treated patients and compared outcomes between those with and without FGF2 genomic amplification. Patients with no FGF2 genomic amplification had significantly longer progression-free survival (PFS) (HR=0.55 (95% CI 0.4, 0.8); p value=0.005) and overall survival (OS) (HR=0.56 (0.3, 0.9); p value=0.02) than patients harboring an FGF2 amplification. We next questioned whether such an observation may extend to genomic amplification of the FGF/FGFR pathway. Similarly, patients with no FGF/FGFR genomic amplification had longer PFS (HR=0.71 (0.8, 0.9), p value=0.004) and OS (HR=0.77 (0.6, 1); p value=0.06). RNA sequencing analysis of tumors between the amplified and non-amplified populations showed distinct expression profiles concerning oncogenic pathways. Importantly, using a cohort of patients untreated with ICB from the The Cancer Genome Atlas, we show that FGF2 and FGF/FGFR genomic amplification were not associated with prognosis, thus demonstrating that we identified a predictive biomarker of immunotherapy resistance.
Insights
Genomic amplification of FGF2 or FGF/FGFR pathways predicts poor response to immune checkpoint blockade (ICB) in metastatic solid cancers. Lack of FGF2/FGFR amplification is associated with longer progression-free and overall survival in patients receiving immunotherapy.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- A novel crosstalk between immunogenic and oncometabolic pathways involving interferon-gamma (IFN-ɣ) and fibroblast growth factor 2 (FGF2) signaling has been identified.
- This pathway can lead to hyperprogressive disease in preclinical models treated with immune checkpoint blockade (ICB).
- IFN-ɣ signaling can have differential effects on tumor cells based on their oncogenic and metabolic characteristics.
Purpose of the Study:
- To investigate the association between genomic amplification of FGF2 or the FGF/FGF receptor (FGFR) pathway and the response to ICB in patients with metastatic solid cancers.
- To determine if FGF2/FGFR genomic amplification serves as a predictive biomarker for immunotherapy resistance.
Main Methods:
- Analysis of a large genomic dataset comprising 545 patients with metastatic solid cancers treated with ICB.
- Comparison of progression-free survival (PFS) and overall survival (OS) between patients with and without FGF2 genomic amplification.
- Assessment of the association between FGF/FGFR pathway genomic amplification and patient outcomes.
- RNA sequencing analysis to compare gene expression profiles between amplified and non-amplified tumor populations.
- Validation using a cohort from The Cancer Genome Atlas (TCGA) for patients not treated with ICB.
Main Results:
- Patients without FGF2 genomic amplification exhibited significantly longer PFS (HR=0.55) and OS (HR=0.56) compared to those with FGF2 amplification.
- Similarly, patients without FGF/FGFR genomic amplification showed longer PFS (HR=0.71) and OS (HR=0.77) than those with amplification.
- Distinct gene expression profiles related to oncogenic pathways were observed between amplified and non-amplified tumor groups.
- FGF2 and FGF/FGFR genomic amplification were not associated with prognosis in immunotherapy-untreated patients from TCGA.
Conclusions:
- Genomic amplification of FGF2 or the FGF/FGFR pathway is associated with significantly poorer outcomes in patients with metastatic solid cancers treated with ICB.
- These findings identify FGF2 and FGF/FGFR genomic amplification as predictive biomarkers of resistance to immunotherapy.
- Understanding these oncometabolic and immunogenic pathway interactions is crucial for optimizing cancer treatment strategies.
