Differential Effect of GLUT1 Overexpression on Survival and Tumor Immune Microenvironment of Human Papilloma Virus Type 16-Positive and -Negative Cervical Cancer

Abstract

Glucose transporter-1 (GLUT1) has been reported as a poor prognosticator associated with radioresistance and immune evasion through metabolic communication in various cancers, but little data is available on cervical cancer. Meanwhile, most cervical cancer is known to be caused by human papilloma virus (HPV), but treatment response and prognosis according to the HPV subtype are also unknown. This hypothesis-generating study was conducted to investigate the prognostic impact of GLUT1 in cervical cancer, in conjunction with HPV subtype. Clinicopathologic factors along with mRNA expression data were obtained using The Cancer Genome Atlas database. Tumor HPV status and immune cell abundance scores were extracted from previous publications. Total 298 patients with appropriate information were analyzed. High GLUT1 expression was associated with old age, squamous cell carcinoma, high tumor stage, pelvic lymph node metastases, and low hysterectomy rate. HPV16 positivity itself was not associated with other factors, except low tumor grade. Multivariate survival analysis revealed that high GLUT1 expression (HR 2.57, p = 0.002) and HPV16 subtype (HR 0.56, p = 0.033) were independent prognostic factors for OS. In the subgroup analysis, poor prognostic impact of high GLUT1 expression was maintained in the HPV16-positive group (p < 0.001), but not in the HPV16-negative group (p = 0.495). Decreased immune cell abundance scores of B cells, CD8 T cells, and Th1 cells by high GLUT1 expression were observed only in the HPV16-positive group. Despite of heterogenous treatments, our results suggested that GLUT1 expression and HPV16 subtype may have an independent prognostic value in cervical cancer. Especially in the HPV16-positive group, GLUT1-mediated immunomodulation might be an important cause of treatment failure. Further proof-of-concept study is warranted to identify novel immunometabolic targets to overcome radioresistance.