title: Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different.
abstract: An HPV infection is involved in the etiology of about 25 % of head and neck squamous cell carcinomas (HNSCC). It has been postulated that a strong antitumoral immune response in HPV-positive tumors represents an important underlying mechanism for their good response to therapy. Recently, the Warburg phenomenon has returned to the center of attention because it affects antitumoral immune response and response to therapy. Accumulation of tumor cell-derived lactate inhibits cytotoxic T cells, as these, analogous to cancer cells, depend on glycolysis and lactate secretion for fulfillment of energy needs. Sparse information exists on the Warburg effect in HNSCC. This study aimed to characterize the metabolic and immunological features of HPV-negative and HPV-positive HNSCC. An immunohistochemical analysis of oropharyngeal carcinomas showed an enhanced antitumoral immune response (CD8/CD4 ratio) together with increased levels of proteins involved in transmembranous metabolite transportation (GLUT1 and CD147) and respiratory metabolism (COX5B) in HPV-positive tumors as compared to HPV-negative tumors. mRNA and Western blot analyses of an HPV-positive and HPV-negative HNSCC cell line revealed metabolic characteristics similar to the in vivo situation. Additionally, the HPV-negative cell line showed stronger extracellular lactate accumulation. In contrast, the HPV-positive cell line presented with better adaption to lactic acidosis suggesting an ability to metabolize lactate. Our results indicate that HPV-positive and HPV-negative carcinomas do not only differ in terms of tumor immune microenvironment, but also in terms of tumor metabolism, characterized by an increased glucose and respiratory metabolism together with decreased lactate accumulation in HPV-positive HNSCC. Therefore, targeting metabolic pathways could represent a promising adjunct in the therapy of HPV-positive HNSCC.
authors.affiliation: Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany, rosemarie.krupar@ukr.de.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Krupar
authors.forename: Katharina
authors.initials: K
authors.lastname: Robold
authors.forename: Doris
authors.initials: D
authors.lastname: Gaag
authors.forename: Gerrit
authors.initials: G
authors.lastname: Spanier
authors.forename: Marina
authors.initials: M
authors.lastname: Kreutz
authors.forename: Kathrin
authors.initials: K
authors.lastname: Renner
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Anja K
authors.initials: AK
authors.lastname: Bosserhoff
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D003576:Electron Transport Complex IV / Q000032:analysis; D051858:Forkhead Transcription Factors / Q000032:analysis; D051272:Glucose Transporter Type 1 / Q000032:analysis / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000235:genetics; D027383:Papillomaviridae / Q000302:isolation & purification*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D007770:L-Lactate Dehydrogenase; C480024:COX5B protein, human; D003576:Electron Transport Complex IV