Abstract
Human papillomavirus (HPV) infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers. Up to 38%–80% of head and neck squamous cell carcinoma (HNSCC) in oropharyngeal location (OPSCC) and nearly all cervical cancers contain the HPV genome which is implicated in causing cancer through its oncoproteins E6 and E7. Given by the biologically distinct HPV-related OPSCC and a more favorable prognosis compared to HPV-negative tumors, clinical trials on de-escalation treatment strategies for these patients have been studied. It is therefore raised the questions for the patient stratification if treatment de-escalation is feasible. Moreover, understanding the crosstalk of HPV-mediated malignancy and immunity with clinical insights from the proportional response rate to immune checkpoint blockade treatments in patients with HNSCC is of importance to substantially improve the treatment efficacy. This review discusses the biology of HPV-related HNSCC as well as successful clinically findings with promising candidates in the pipeline for future directions. With the advent of various sequencing technologies, further biomolecules associated with HPV-related HNSCC progression are currently being identified to be used as potential biomarkers or targets for clinical decisions throughout the continuum of cancer care.
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Introduction
High-risk human papillomavirus (HR-HPV) infection leads to the development of human cancers in a variety of anatomical squamous tissue sites, including the head and neck regions. The incidence of HPV-related head and neck squamous cell carcinoma (HNSCC), especially oropharyngeal squamous cell carcinoma (OPSCC), has increased in the United States and Europe (Chaturvedi et al. 2013; Tinhofer et al. 2015; Wittekindt et al. 2019; Zamani et al. 2020). In some regions, HPV-related OPSCC accounts for 38%–80% of OPSCCs and 30% of HNSCCs (Boscolo-Rizzo et al. 2013; Chaturvedi et al. 2013; de Martel et al. 2020; Leemans et al. 2018) (Table 1). In particular, patients with HPV-related OPSCC have a better prognosis than those with HPV-negative OPSCC (Leemans et al. 2018). The proportion of comparatively younger patients is high among patients with HPV-related OPSCC (Leemans et al. 2018). Moreover, HPV-related OPSCCs are more sensitive to chemoradiotherapy and immune checkpoint blockade (ICB) treatments than HPV-unrelated tumors (Leemans et al. 2018). With the accumulated understanding of the new entity of HPV-related OPSCC, a new staging system in the 8th edition of the American Joint Committee on Cancer (AJCC) has been established toward a deintensified treatment protocol to reduce long-term associated morbidity for patients with HPV-related OPSCC. However, recent phase III clinical trials (RTOG 1016 and De-ESCALaTE) have shown that a number of patients with HPV-related OPSCC who received deintensified treatment had an inferior outcome compared to those who received standard care (Gillison et al. 2019b; Mehanna et al. 2019). Moreover, patients with HPV-related HNSCC at multiple sites, defined as one HPV-positive primary OPSCC and a second primary of any head and neck site, demonstrated distinct characteristics (i.e., a lower T and N stage) compared to patients with one primary tumor (Joseph et al. 2013; Strober et al. 2020). These observations lead to a further discussion on the feasibility of the current design of the de-escalation treatment protocol in clinical trials and highlight the necessity to refine the stratification strategy for patients with HPV-related HNSCC, in particular for OPSCC (Ventz et al. 2019).
HPV-driven oncogenic processes are characterized by HPV oncoproteins E6 and E7, which induce p53 and retinoblastoma (Rb) degradation, consequently leading to a deregulation of the cell cycle and an inhibition of apoptosis (Wittekindt et al. 2018). A plethora of data have been recently accumulated for different incidences of gene mutations and chromosomal aberrations between HPV-related and HPV-unrelated HNSCCs (Pickering et al. 2014; Dsouza et al. 2014).
A The HPV genomic structure (use HPV 16 as an example). The ORFs encoding the early (blue) and late (yellow) genes are marked. B The life cycle of HPV starts with viral infection at the basal cells through trauma and the viral genomes are maintained at low copy number level in undifferentiated cell. Upon cell differentiation, the viral genomes become amplified and virion assembly ensues, resulting in the release of viruses in the cornified layer. C The contribution of different high-risk HPV genotypes to head and neck squamous carcinoma (Tumban 2019).
HPV Genome and Expression
The genetic information of HPVs is carried by their circular, double-stranded DNA genome, which has a size of approximately 8,000 base pairs (Zheng and Baker 2006). According to the genome data compiled in the Papillomavirus Episteme database (https://pave.niaid.nih.gov/), there are more than 225 distinct genotypes of HPVs, which are classified according to the DNA sequence of the L1 gene. To be recognized as a new genotype, the L1 region sequence has to be more than 10% different from its closest member. Despite the sequence variation, the HPV genome structure is similar for all genotypes and is organized into three regions (Fig. 1). The early gene region contains several overlap** open reading frames (ORFs) denoted E1, E2, E4, E5, E6, E7 and E8 (E5 and E8 not present in all genotypes) that code for nonstructural and regulatory proteins involved in various processes of the virus life cycle, such as viral replication and transactivation of gene expression. Currently, 12–15 genotypes of HPVs are considered oncogenic for certain types of cancers, with the early proteins E6 and E7 playing key roles in oncogenesis and thus are two multifunctional viral oncoproteins (Zheng and Wang 2011; Roman and Munger 2013; Vande Pol and Klingelhutz 2013; Wang et al. 2015). HPV integration can lead to host genomic instability, such as deletions, inversions, and chromosomal translocations (Akagi et al. 2015; Walline et al. 2016; Koneva et al. 2018). Moreover, viral integration into cellular genes was commonly identified in recurrent HPV16-positive OPSCC patients, and these cellular genes are related to cancer-associated signaling pathways or mechanisms (Walline et al. 2016). Integrated viral DNA copies could be in tandem. Viral DNA integration through the disruption of the viral E2 region leads to increased transcription of viral E6 and E7. Tumors with HPV DNA integration differ from HPV integration-negative tumors by different patterns of DNA methylation and gene expression profiles (Parfenov et al. 2014). Recently, Zapatka et al. found that HPV 16 and HPV 18 integration events in cervical cancer and HNSCC were associated with local variations and genomic rearrangements based on the Pan-Cancer Analysis of Whole Genomes Consortium (Zapatka et al. 2020).
HPV integration inducing genome instability is hypothesized to be a secondary genetic event in the carcinogenesis of HPV-associated HNSCC. HPV infection is associated with increased expression of the APOBEC genes APOBEC3A and APOBEC3B but exclusively with known driver genes such as TP53, CDKN2A and TERT (Kondo et al. 2017; Zapatka et al. 2020). These findings suggest a possible role of APOBECs in HPV-induced carcinogenesis, i.e., the activity of APOBECs as C-to-U RNA editing enzymes contributes to alterations in host genome expression, and APOBEC3A increases tumorigenesis in vivo (Burns et al. 2013; Wallace and Münger 2018; Law et al. 2020). In addition, as part of the immune defense system, APOBEC3A can sensitize cancer cells to cisplatin treatment by activating base excision repair and mediating the repair of cisplatin interstrand crosslinks (Conner et al. 2020). These results suggest a role of impaired antiviral defense in driving the carcinogenesis of HPV-related HNSCC. HPV16 insertions also lead to the amplification of the PIM1 serine/threonine kinase gene in HNSCC cell lines (Broutian et al. 2020).
A Immune escape of HPV-related head and neck squamous cell carcinoma (HNSCC) and potential approaches to improve immunotherapeutic effects against HPV-related tumor. HLA: human leukocyte antigen; TCR: T-cell receptor; PD-1: programmed cell death protein 1; PDL-1: programmed death-ligand 1; LMP2: low molecular weight protein 2; TAP1: antigen processing subunit 1; STING: stimulator of interferon genes. B The platform of risk stratification for HPV-related HNSCC. IHC: immunohistochemical staining.
High PD-1 expression was significantly associated with HPV-positive HNSCC in an analysis of a TCGA dataset (Lyu et al. 2019). PDL1 expression in HPV-related HNSCC ranges from ~49.2% to ~75% according to a report (Outh-Gauer et al. 2020). Increased PD1 expression on T cells is correlated with HR-HPV infection in the pathogenesis of cervical intraepithelial neoplasias (CINs) (Yang et al. 2013, 2017). Additionally, a higher HPV 16 viral load is correlated with high CD8 + and PD-1 + TIL expression in anal squamous cell cancer (ASCC) (Balermpas et al. 2017). PDL1 expression is significantly enhanced in relation to HPV positivity (i.e., HPV16 E7 oncoprotein) in CINs and cervical cancer compared to normal cervical epithelia (Yang et al. 2013; Mezache et al. 2015). Taken together, these findings suggest that PD1/PDL1 pathways may be activated by HR-HPV (i.e., E5, E6 and E7 oncoproteins) for HPV-related cancers. HPV E6/E7-induced master regulators (ENO1, PRDM1, OVOL1, and MNT) are positively correlated with PD-L1 and TGFB1 expressions in cervical cancer (Qin et al. 2017). The activation of the PD1/PDL1 pathway by HR-HPV can further inhibit Th1 cytokine IFN-c and IL-12 expressions and upregulate TH2-type cytokine and IL-10 expressions, consequently leading to immunosuppression and CIN progression (Wakabayashi et al. 2019; Zhou et al. 2019). Remarkably, the reactivity of nonviral tumor antigen-specific T cells, including mutated neoantigen or cancer germline antigen, together with HPV oncoprotein-reactive T cells was observed in HPV-associated metastatic cervical cancer patients with complete regression after tumor-infiltrating adoptive T cell therapy (Stevanović et al. 2017). Thus, it would be interesting to understand the crosstalk of HPV-mediated immunosuppression and immune checkpoint activities for further development of therapeutic strategies.
Efforts to define HPV-related HNSCC responses to ICB treatments were initially assessed based on recent clinical trials (Bauml et al. 2017; Ferris et al. 2018; Burtness et al. 2019). In CheckMate 141, a better median overall survival among patients receiving nivolumab treatment was found to be associated with HPV-positive tumors with PDL1-positive expression (Ferris et al. 2018). In KEYNOTE-012, the response rate to pembrolizumab treatment varied among HNSCC patients with PD-L1 positivity, with a higher response rate in HPV-positive tumors than in HPV-negative tumors (Seiwert et al. 2016). A recent meta-analysis demonstrated an improved response rate to ICB treatment among patients with HPV-positive HNSCC and a higher OS in patients with PDL1-positive HNSCC (Galvis et al. 2020). However, the treatment efficacy of atezolizumab in a phase I trial was found independent of HPV status and PD-L1 expression level (Colevas et al. 2018). Because of the limited size of each study, the findings should be interpreted with caution.
The development of combination therapy by employing different immune priming approaches has the potential to improve effective immune responses in HPV-related cancer patients who receive immunotherapy. For example, targeting HPV16/18 E6/E7 by a DNA vaccine with an IL12 adjuvant is able to generate durable HPV16/18 antigen-specific cytotoxic T cells and tumor immune responses in patients with p16 + locally advanced HNSCC (Aggarwal et al. 2019). One patient who developed metastatic disease received anti-PD1 nivolumab treatment and had a complete response (Aggarwal et al. 2019). This phase I/IIa clinical trial, in line with other vaccination strategies targeted to HR-HPV E6/E7 oncoproteins, demonstrates a complementary approach to improve immunotherapy outcomes (Aggarwal et al. 2019; Massarelli et al. 2019; Xu et al. 2020a). The NLRX1 signaling pathway was found to be associated with HPV16 E7-mediated IFN-I suppression and TIL infiltration in HNSCC (Luo et al. 2020). NLRX1 depletion leads to a turnover of HPV16 E7, potentiating STING/IFN-I suppression and consequently improving tumor control (Luo et al. 2020). Clinical trials (NCT02675439, NCT03172936, and NCT03010176) utilizing a combination of a STING agonist plus anti-CTLA-4 or anti-PD1 ICB treatments are underway (Luo et al. 2020). In addition, it has been demonstrated that HPV E5 mediates resistance to anti-PD-L1 immunotherapy, which is due to acquired loss of major histocompatibility complex (MHC) expression (Sharma et al. 2017; Miyauchi et al. 2020). Rimantadine, an FDA-approved antiviral drug to treat influenza that was recently found to induce an antitumor response, could increase MHC expression in HPV E5-expressing HNSCC (Miyauchi et al. 2020) (Fig. 2A). However, rimantadine in combination with radiation and PD-L1 checkpoint blockade treatment did not show a synergistic effect (Miyauchi et al. 2020). E2-derived CD8 T cell epitopes were found in patients with HPV-related HNSCC (Krishna et al. 2018). Wieland et al. demonstrated that the E2 protein is a major target of the humoral immune response in the TME of HPV-related HNSCC (Wieland et al. 2020). Thus, a combination of HPV E2, E6 and E7 as targets needs to be explored for future immunotherapeutic approaches. Alternatively, innovations in nanotechnology will likely synergize with immunotherapy to elicit a robust treatment response in HNSCC (Xu et al. 2020a). For example, the PC7A nanovaccine, an ultra-pH -sensitive nanoparticle synergistic with anti-PD1 antibodies, can improve antitumor immunity and survival in HPV-E6/E7 TC-1 tumors (Luo et al. 2017). Another example is an HR-HPV nanovaccine formulated with CL 1,2-dioleoyl-3-trimethyl-ammonium-propane (DOTAP), and long HR-HPV peptides can successfully boost Ag-specific CD8 T cell responses, induce complete tumor regression through a type I IFN response in HPV-E6/E7 TC-1 tumor models and synergize with an anti-PD1 checkpoint inhibitor (Gandhapudi et al. 2019). It should be noted that chemoradiotherapy decreases HPV-specific T cell responses and increases PD-1 expression on CD4 + T cells in patients with HPV-related oropharyngeal cancer (Parikh et al. 2014). Accordingly, a future analysis of patients with HPV-related HNSCC who have and have not responded to ICB treatment would provide additional insights for targeted immunotherapy as well as deintensified treatments.
Patient Stratification for the Deintensified Treatments
To formulate a diagnosis for HPV-related HNSCC, methods based on p16 immunohistochemical (IHC) staining, quantitative polymerase chain reaction (qPCR)-based HR-HPV DNA or RNA testing, and HPV DNA or RNA in situ hybridization (ISH) have been established. In 2018, the College of American Pathologists (CAP) and American Society of Clinical Oncology (ASCO) released guidelines that HR-HPV testing should be performed for OPSCC and cervical nodal metastases of unknown primary tumors (Fakhry et al. 2018; Lewis et al. 2018). Protein p16 IHC staining was recommended prior to other HPV testing with a cutoff of 70% nuclear and cytoplasmic positivity (Fig. 2B). For HPV-related tumors, the HR-HPV E7 oncoprotein increases expression of histone lysine demethylase 6B (KDM6B) and induces pRb degradation, thereby leading to H3K27-specific demethylation (derepression) of p16 promoter to enhance high level of p16 expression for proliferation of the cancer cells lacking the G1 checkpoint due to viral E7-induced loss of pRb (McLaughlin-Drubin et al. 2013; Pal and Kundu 2019). However, Albers et al. demonstrated that a subgroup of HNSCC with HPV-DNA+/p16− had poor survival compared to subgroups with HPV-DNA+/p16+ and HPV-DNA−/p16+, which suggests a biologically different subtype independent of HPV status (Albers et al. 2017). A recent survival analysis further revealed that 60.6% of p16+ HPV-DNA− OPSCCs did not resemble HPV16-driven but HPV-negative tumors (Wagner et al. 2020). Moreover, gene signatures such as TP53 mutations are indistinguishable between tumors with HPV DNA+RNA− and those with HPV DNA− (Wichmann et al. 2015). As indicated above, some patients who received deintensified treatments failed to show an improvement in clinical trials. Thus, pathology-based HPV testing beyond p16 IHC staining remains to be established. HPV RNA ISH, by which viral E6/E7 mRNA has been detected, showed a better survival prediction and a higher specificity than p16 IHC staining (Lewis 2020). Additionally, the sensitivity of HPV RNA ISH is higher than that of HPV DNA ISH (91% vs. 65%) (Kerr et al. 2015). The performance of HPV RNA ISH testing in stratifying OPSCC patients is worth further validation (Lewis 2020).
While current HPV-specific testing warrants further improvement, a better understanding of the biology of HPV-related HNSCC is necessary for us to identify new biomarkers correlated with disease outcomes and to predict treatment response signatures, especially for immunotherapy. For example, the latency effect of tobacco smoking exposure appears more profound in HPV-related HNSCC individuals who start smoking before sexual activity when compared to those who start after (Madathil et al. 2020). High levels of TILs that reflect the immune response can stratify HPV-related OPSCC patients into high-risk and low-risk groups for survival (Ward et al. 2014). Interestingly, a prognostic model was further developed, including three covariates (TIL levels, heavy smoking, and T-stage) in which low TIL levels, heavy smoking, and late T-stage were related to poor outcome for HPV-related OPSCC (Ward et al. 2014). HPV integration status based on RNA-seq data can differentiate survival between HPV integration-positive and HPV-negative HNSCC patients (Koneva et al. 2018). Most importantly, a set of immune-related gene signatures enriched in HPV-positive but HPV integration-negative tumors are distinguishable from those in HPV integration-positive tumors (Koneva et al. 2018). The lower E2F target gene expression predicted by reduced E7 levels is associated with disease recurrence through patient-derived xenograft (PDX) models for HPV-related HNSCC (Facompre et al. 2020). HPV + tumors have been related to an inflamed/mesenchymal phenotype. By analyzing RNA-sequencing data from TCGA, studies show that HPV+ HNSCC exhibited an upregulation of MHC-I- and MHC-II-related genes, which may be induced by IFN-gamma, a strong Th1 response and higher expression of the T cell “exhaustion markers” LAG3, PD1, TIGIT, and TIM3 with coordinately expressed CD39 compared to HPV− tumors at the transcription level (Gameiro et al. 2018, 2019; Ruicci et al. 2019b). However, histopathologic intratumor immune cell heterogeneity is also seen within HPV-related HNSCC. Two subtypes of HPV-related HNSCC have been identified, with an inflamed/mesenchymal phenotype enriched in CD8+ T cell infiltration leading to better survival than a classic phenotype characterized by keratinization and higher proliferation (Keck et al. 2015). In addition, cancer stem cells (CSC), a subpopulation within the bulk tumor entity of HNSCC, have shown their characteristics such as less antigen expression, processing, and presentation to induce the immunogenicity and immunosuppression (Qian et al. 2020). Further, studies demonstrate that HNSCC patients with the HPV+/CSClow phenotype had better outcomes than HPV−/CSChigh group (Reid et al. 2019). Given the paucity of molecular biomarkers, combined insights into genetic, epigenetic and transcriptional alterations can provide robust candidate biomarkers to stratify patients further and to predict treatment outcomes.
Conclusions
The molecular landscapes of HNSCC have largely been defined during the past decade. The intratumor heterogeneity (e.g., genetic, epigenetic and histopathologic) of HPV-related HNSCC has been identified as contributing to the pathophysiology of the disease. This variability contributes to the range of treatment responses observed for both established clinical practice and clinical trials. The clinical translation of these findings may help for dynamic risk restratification of HPV-related HNSCC patients with new molecular biomarkers. The management of HPV-related HNSCC is changing, and substantial research focusing on discovery approaches to cancer diagnostics and prognostic evaluations is required (Bigelow et al. 2020).
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This work was supported by grants from the Medical and the Health Science Project of Zhejiang Province (2019KY327) and Guangji Talents Foundation Award (E) of Zhejiang Cancer Hospital.
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Dong, H., Shu, X., Xu, Q. et al. Current Status of Human Papillomavirus-Related Head and Neck Cancer: From Viral Genome to Patient Care. Virol. Sin. 36, 1284–1302 (2021). https://doi.org/10.1007/s12250-021-00413-8
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DOI: https://doi.org/10.1007/s12250-021-00413-8