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Review
. 2021 Oct;31(4):274-285.
doi: 10.1016/j.semradonc.2021.02.009.

Biology of the Radio- and Chemo-Responsiveness in HPV Malignancies

Michael T Spiotto  1 , Cullen M Taniguchi  2 , Ann H Klopp  2 , Lauren E Colbert  2 , Steven H Lin  2 , Li Wang  2 , Mitchell J Frederick  3 , Abdullah A Osman  4 , Curtis R Pickering  4 , Steven J Frank  2
Affiliations
Review

Biology of the Radio- and Chemo-Responsiveness in HPV Malignancies

Michael T Spiotto et al. Semin Radiat Oncol. 2021 Oct.

Abstract

In multiple anatomic sites, patients with cancers associated with the Human Papillomavirus (HPV) experience better locoregional control and overall survival after radiotherapy and/or chemoradiotherapy than patients with HPV-negative cancers. These improved outcomes suggest that relatively unique biological features in HPV-positive cancers may increase sensitivity to DNA damaging agents as well as an impaired DNA damage response. This review will address potential biological mechanisms driving this increased sensitivity of HPV-positive cancer to radiation and/or chemotherapy. This review will discuss the clinical and preclinical observations that support the intrinsic radiosensitivity and/or chemosensitivity of HPV-positive cancers. Furthermore, this review will highlight the molecular mechanisms for increased radiation sensitivity using the classical "4 Rs" of radiobiology: repair, reassortment, repopulation, and reoxygenation. First, HPV-positive cancers have increased DNA damage due to increased oxidative stress and impaired DNA damage repair due to the altered activity TP53, p16, TIP60, and other repair proteins. Second, irradiated HPV-positive cancer cells display increased G2/M arrest leading to reassortment of cancer cells in more radiosensitive phases of the cell cycle. In addition, HPV-positive cancers have less radioresistant cancer stem cell subpopulations that may limit their repopulation during radiotherapy. Finally, HPV-positive cancers may also have less hypoxic tumor microenvironments that make these cancers more sensitive to radiation than HPV-negative cells. We will also discuss extrinsic immune and microenvironmental factors enriched in HPV-positive cancers that facilities responses to radiation. Therefore, these potential biological mechanisms may underpin the improved clinical outcomes often observed in these virally induced cancers.

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Figures

Figure 1.
Figure 1.. Comparison of HPV-positive and HPV-negative cancers in relation to DNA repair, reassortment, reoxygenation and repopulation.
Compared to HPV-negative cancers, irradiated HPV-positive cancers have impaired DNA repair as measured by persistent gH2AX and 53BP1 accumulation, G2/M arrest, decreased tumor hypoxia and lower stem cell populations. Created with BioRender.com.
Figure 2.
Figure 2.. Summary of the major DNA damage repair pathways impaired in HPV-positive cancers.
The HPV oncogene E6 inhibits DNA damage response and DNA damage repair via inhibition of TP53, Tip50 and XRCC1. E7 inhibits RB1 to impair the non-homologous end joining repair pathway as well as to activate p16 which impairs homologous repair. Genes colored in orange represent HPV viral oncogenes. Genes colored in yellow represent cellular genes/pathways involved in DNA repair that are direct HPV oncogene targets. Genes colored in green represent cellular genes/pathways involved in DNA repair that are indirect HPV oncogene targets. Created with BioRender.com.
Figure 3.
Figure 3.. Induction of HPV oncogenes E6/E7 increases γH2AX in a primary oral tumor model.
HPV-negative and HPV-positive oral tumor described in [33] were assessed for gH2AX (red) and DAPI (blue) and assessed using immunofluorescence.
Figure 4.
Figure 4.. Summary of the major pathways by which HPV alters the cell cycle in response to radiotherapy.
E6 inhibits p53 which may induce G2/M arrest via p27and p21. E7 may activate the G1/S transition via E2F transcription factors. Radiation can activate G2M arrest in HPV-positive cancers via CHK1 and CHK2 pathways. Small molecule inhibitors of indicated are listed. Genes colored in orange represent HPV viral oncogenes. Genes colored in yellow represent cellular genes/pathways involved in DNA repair that are direct HPV oncogene targets. Genes colored in green represent cellular genes/pathways involved in DNA repair that are indirect HPV oncogene targets.Created with BioRender.com.
Figure 5.
Figure 5.. Potential immune microenvironmental mechanisms that sensitize HPV-positive cancers to radiation.
Differences in the immune microenvironment may sensitize HPV-positive cancers to radiation by increased M1 macrophage populations, loss of CD47 after irradiation and increased expression of PD-L1 that may be targeted by checkpoint inhibitors to target cancer cells expressing unique viral antigens.
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