Metformin Effects on FOXP3+ and CD8+ T Cell Infiltrates of Head and Neck Squamous Cell Carcinoma

• Published in: The Laryngoscope 2020-09, Vol.130 (9), p.E490-E498
• Main Authors: Amin, Dev, Richa, Tony, Mollaee, Mehri, Zhan, Tingting, Tassone, Patrick, Johnson, Jennifer, Luginbuhl, Adam, Cognetti, David, Martinez‐Outschoorn, Ubaldo, Stapp, Robert, Solomides, Charalambos, Rodeck, Ulrich, Curry, Joseph
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antidiabetics; CD8 Antigens - immunology; Chemotherapy, Adjuvant; Female; Forkhead Transcription Factors - immunology; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - immunology; Human papillomavirus; Humans; Immunohistochemistry; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Male; metformin; Metformin - pharmacology; Middle Aged; Preoperative Period; Retrospective Studies; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - immunology; tumor infiltrating lymphocytes; tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology
• ISSN: 0023-852X; 1531-4995
• DOI: 10.1002/lary.28336

Objectives Alterations of cellular metabolism have been implicated in immune dysfunction in the tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC). Metformin has recently emerged as a candidate of interest for combination with immunotherapy in HNSCC. This study investigated the effect of metformin on immune cell infiltrates of HNSCC. Methods Retrospective analysis of T cell infiltrates in primary tumor specimens from patients enrolled in a clinical window of opportunity trial of presurgical metformin. Metformin was titrated to a standard diabetic dose (2000 mg/day) for a minimum of 9 days (mean 13.6 days) prior to surgical resection. Pre and posttreatment surgical specimens from 36 patients (16 HPV+, 20 HPV−) were comparatively analyzed. FOXP3+ and CD8+ immune cell infiltrates in the tumor and peritumoral stroma of pre and posttreatment HNSCC specimens were quantified by digital image analysis using Visiopharm software. Results Metformin treatment was associated with a 41.4% decrease in FOXP3+ T cells in intratumor regions of interest (P = .004) and a 66.5% increase in stromal CD8+ T cells at the leading edge of the tumor (P = .021) when compared to pretreatment biopsies. This was reflected in increased CD8+/FOXP3+ cell ratios within the tumor (P