Metformin Clinical Trial in HPV+ and HPV– Head and Neck Squamous Cell Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate

Frontiers in Oncology

Ulrich Rodeck¹  My G. Mahoney¹  Andrew South¹  Jennifer Johnson²  Diana Whitaker-Menezes²  Ubaldo Martinez-Outschoorn²  Larry Harshyne³  Alexander Knops⁴  Adam Luginbuhl⁴  Joseph M. Curry⁴  Dev Amin⁴  David Cognetti⁴  Patrick Tassone⁴  Mehri Mollaee⁵  Nancy Philp⁵  Madalina Tuluc⁵  Tingting Zhan⁶ 

[1]Department of Dermatology and Cutaneous Biology, Thomas Jefferson University Philadelphia, Philadelphia, PA, United States

[2]Department of Medical Oncology, Thomas Jefferson University Philadelphia, Philadelphia, PA, United States

[3]Department of Neurological Surgery, Thomas Jefferson University Philadelphia, Philadelphia, PA, United States

[4]Department of Otolaryngology Head and Neck Surgery, Thomas Jefferson University Philadelphia, Philadelphia, PA, United States

[5]Department of Pathology, Anatomy and Cell biology, Thomas Jefferson University Philadelphia, Philadelphia, PA, United States

[6]Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University Philadelphia, Philadelphia, PA, United States

关键词: head and neck cancer;    squamous cell carcinoma;    metformin;    tumor microenvironment;    immune infiltrate;    HPV;   

DOI  :  10.3389/fonc.2018.00436

来源: DOAJ

【 摘 要 】

Background: Metformin, an oral anti-hyperglycemic drug which inhibits mitochondrial complex I and oxidative phosphorylation has been reported to correlate with improved outcomes in head and neck squamous cell carcinoma (HNSCC) and other cancers. This effect is postulated to occur through disruption of tumor-driven metabolic and immune dysregulation in the tumor microenvironment (TME). We report new findings on the impact of metformin on the tumor and immune elements of the TME from a clinical trial of metformin in HNSCC.Methods: Human papilloma virus—(HPV–) tobacco+ mucosal HNSCC samples (n = 12) were compared to HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples (n = 17) from patients enrolled in a clinical trial. Apoptosis in tumor samples pre- and post-treatment with metformin was compared by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Metastatic lymph nodes with extra-capsular extension (ECE) in metformin-treated patients (n = 7) were compared to archival lymph node samples with ECE (n = 11) for differences in immune markers quantified by digital image analysis using co-localization and nuclear algorithms (PD-L1, FoxP3, CD163, CD8).Results: HPV–, tobacco + HNSCC (mean Δ 13.7/high power field) specimens had a significantly higher increase in apoptosis compared to HPV+ OPSCC specimens (mean Δ 5.7/high power field) (p < 0.001). Analysis of the stroma at the invasive front in ECE nodal specimens from both HPV—HNSCC and HPV+ OPSCC metformin treated specimens showed increased CD8+ effector T cell infiltrate (mean 22.8%) compared to archival specimens (mean 10.7%) (p = 0.006). Similarly, metformin treated specimens showed an increased FoxP3+ regulatory T cell infiltrate (mean 9%) compared to non-treated archival specimens (mean 5%) (p = 0.019).Conclusions: This study presents novel data demonstrating that metformin differentially impacts HNSCC subtypes with greater apoptosis in HPV—HNSCC compared to HPV+ OPSCC. Moreover, we present the first in vivo human evidence that metformin may also trigger increased CD8+ Teff and FoxP3+ Tregs in the TME, suggesting an immunomodulatory effect in HNSCC. Further research is necessary to assess the effect of metformin on the TME of HNSCC.

【 授权许可】

Unknown