Hypoxia and Its Influence on Radiotherapy Response of HPV-Positive and HPV-Negative Head and Neck Cancer

SIMPLE SUMMARY: HPV-positive HNSCCs are characterized by a different biology and demonstrate better therapy response and survival compared to alcohol/tobacco-related HNSCCs. Although we have a better understanding of the biology of both groups of HNSCC, the biological factors, especially environmental factors associated with the increased radiotherapy response, are still unclear. In this manuscript, we review the effects of an important microenvironmental factor, namely, low oxygen levels, also known as hypoxia, on the radiotherapy response and the tumor biology of HPV-positive and HPV-negative HNSCCs. In addition, we provide an overview of the current strategies to detect and target hypoxia, with a description of important clinical trials. ABSTRACT: Head and neck squamous cancers are a heterogeneous group of cancers that arise from the upper aerodigestive tract. Etiologically, these tumors are linked to alcohol/tobacco abuse and infections with high-risk human papillomavirus (HPV). HPV-positive HNSCCs are characterized by a different biology and also demonstrate better therapy response and survival compared to alcohol/tobacco-related HNSCCs. Despite this advantageous therapy response and the clear biological differences, all locally advanced HNSCCs are treated with the same chemo-radiotherapy schedules. Although we have a better understanding of the biology of both groups of HNSCC, the biological factors associated with the increased radiotherapy response are still unclear. Hypoxia, i.e., low oxygen levels because of an imbalance between oxygen demand and supply, is an important biological factor associated with radiotherapy response and has been linked with HPV infections. In this review, we discuss the effects of hypoxia on radiotherapy response, on the tumor biology, and the tumor microenvironment of HPV-positive and HPV-negative HNSCCs by pointing out the differences between these two tumor types. In addition, we provide an overview of the current strategies to detect and target hypoxia.