Molecular and cellular mechanisms of human papillomavirus influence on cancer sensitivity to radiation therapy. Review

The article presents review of literature data and results of our own studies devoted to elucidating the molecular and cellular mechanisms of influence of human papillomaviruses (HPV) on the effectiveness of radiation therapy (RT) of HPV-associated malignant neoplasms, including, first of all, cervical and oropharyngeal cancer. The data are systematized from the point of view of HPV influence on 6 main factors (so-called 6Rs), determining the response of cells/tissues to fractionated irradiation and, ultimately, affecting the effectiveness of RT (reparation, reoxygenation, redistribution across cell cycle phases, repopulation, radiosensitivity, reactivation of the immune response). Compared with HPV-negative tumors, HPV-positive tumors demonstrate higher sensitivity to sparsely ionizing radiation due to decreased efficiency of homologous DNA damage repair (R1), higher oxygenation and suppression of antioxidant defense (R2), impaired cell cycle control (R3), features of cancer stem cell regulation that ensure post-radiation repopulation (R4), and higher intrinsic radiosensitivity (R5). Viral proteins E6 and E7 have a broad spectrum of action on the state of innate and adaptive antitumor immunity, therefore significant differences were demonstrated in immunological profile of HPV-positive and HPV-negative tumors, as well as in efficiency of combined radioimmunotherapy of cancer patients with different HPV status. However, the effects of HPV on reactivation of antitumor immune response (R6) during fractionated irradiation has not been sufficiently studied. Thus, HPV have a significant impact on almost all known factors (at least 5 out of 6 Rs) determining the effectiveness of RT using sparsely ionizing radiation. Analysis of the mechanisms of such impact suggests that differences in effectiveness of RT of HPV-positive and HPV-negative tumors can, at least partially e leveled out when using densely ionizing radiation.