Hans, Stéphane

Lechien, Jerome R

Mouawad, Francois

Saussez, Sven

ORBi UMONS

Frontiers in Oncology | www.frontiersin.orgEdited and reviewed by:Jan Baptist Vermorken,University of Antwerp, Belgium*Correspondence:Jerome R. LechienJerome.Lechien@umons.ac.beSpecialty section:This article was submitted toHead and Neck Cancer,a section of the journalFrontiers in OncologyReceived: 14 October 2021Accepted: 31 January 2022Published: 03 March 2022Citation:Lechien JR, Mouawad F, Hans S andSaussez S (2022) Editorial: Advancesin the Involvement of HumanPapilloma Virus in Head and NeckSquamous Cell Carcinoma.Front. Oncol. 12:795280.doi: 10.3389/fonc.2022.795280EDITORIALpublished: 03 March 2022doi: 10.3389/fonc.2022.795280Editorial: Advances in theInvolvement of Human PapillomaVirus in Head and Neck SquamousCell CarcinomaJerome R. Lechien1,2,3*, Francois Mouawad4, Stéphane Hans2 and Sven Saussez1,51 Department of Human Anatomy and Experimental Oncology, Faculty of Medicine, UMONS Research Institute for HealthSciences and Technology, University of Mons (UMons), Mons, Belgium, 2 Department of Otolaryngology-Head and NeckSurgery, Foch Hospital, School of Medicine, University Paris Saclay, Paris, France, 3 Department of Otolaryngology, ElsanHospital, Paris, France, 4 Department of Otolaryngology-Head and Neck Surgery, CHRU de Lille, Hopital Claude Huriez,Lille, France, 5 Department of Otolaryngology-Head and Neck Surgery, Centre Hospitalier Universitaire (CHU) Saint-Pierre,Brussels, BelgiumKeywords: cancer, head neck, HPV, human papillomavirus, carcinoma, otolaryngology, head neck, surgeryEditorial on the Research TopicAdvances in the Involvement of Human Papilloma Virus in Head and Neck SquamousCell CarcinomaBACKGROUNDHead and neck squamous cell carcinomas (HNSCC) are the sixth most common cancers in malesand the eighth most common in females worldwide, accounting for over 890,000 new cases in 2017(1, 2). HNSCCs represent 5.3% of all cancers. From a mortality standpoint, they involve more than500,000 deaths worldwide, representing 5.3% of all cancer deaths (2). Irrespective to the worldregion, the most prevalent HNSCCs in 2017 were lip and oral cavity (390,000 new cases), laryngeal(211,000 new cases), pharyngeal (179,000 new cases) and nasopharyngeal (110,000 new cases)carcinomas (2). The main risk factors for HNSCCs are alcohol and tobacco consumption andpersistent infection with human papillomavirus (HPV) that is associated with the rising incidence oforopharyngeal squamous cell carcinoma (OSCC) in the United States and Europe (3, 4). Theincidence of HPV-induced HNSCC depends on the world region and the method used to assess thepresence of HPV (5). The incidence of HPV-induced HNSCC has increased since the 80s (5).HPV infection is predominantly attributable to subtypes HPV-16 and HPV-18 even if there isgeographical heterogeneity between continents (3, 6, 7). Young, nondrinking and nonsmokingindividuals with HPV-induced OSCC often have advanced carcinoma, but they have a betterprognosis compared with patients with tobacco- and alcohol-induced OSCC (6, 7). Themechanisms underlying the better prognosis of patients with HPV-induced HNSCC remainpoorly understood and may involve interactions between HPV antigens and the host-immunesystem, leading to an improved responses of immune cells against tumor (8). In that way, anincreasing number of studies reported significant differences in the composition of tumor-infiltrating immune cells in HPV-positive and HPV-negative HNSCC (8). Most authors recognizedthat the overexpression of some immune cells may be considered as a significant prognostic factor forHNSCC patients (8). In this Research Topic, several research groups published clinical and experimentalstudies about the involvement of HPV in the development of OSCC and non-OSCC.2March 2022 | Volume 12 | Article 7952801Lechien et al. Editorial: HPV in Head & Neck CancerIMMUNOLOGICAL FEATURES OFHPV-INDUCED CARCINOMAThe better survival outcomes of patients with HPV-positive OSCCmay be explained by immunological differences between HPV-positive and HPV-negative HNSCCs. The HPV infection isassociated with an increased CD8+ T tumor cell infiltration andPD-1 expression by CD8+ T cells in both OSCC and non-OSCC,which is associated with better overall survival (OS). The interactionbetween the tumor environment and CD8+ T cells is mediatedthrough many cytokines, including IFN-g and IL-2, -4, -8, -12 and-17 (9, 10). Recent studies supported interactions between CD8+and CD4+ T cells in HPV-positive HNSCC (8). Precisely, in tumorenvironment, CD4+ T cells may be converted into Th17 cells,which could potentiate the cytotoxic effects of CD8+ T cells againstHPV-induced tumor cells (8). M1 and M2 macrophages areadditional immune cells that may have an important role inHPV-induced carcinogenesis (11). M2 macrophages are involvedin the enhancement of immunosuppression through thestimulation of regulatory T cells (Tregs) that induces a favorableenvironment for tumor growth through the secretion of TGF-b,TNF-a, and IL-10 (8). In HPV-negative HNSCC, an increasedproportion of M2 cells is an important factor underlying theimprovement of OS (8). The involvement of Foxp3 Tregs inHPV-positive and HPV-negative HNSCC remains uncertain.Indeed, several researches showed that an increase of Tregs inHPV-positive HNSCC environment was associated with improvedOS (8, 12), while others reported similar findings in HNSCC but noinfluence of the HPV status (8, 13). Foxp3 Tregs may inhibit theprotumoral effects of inflammatory immune cells, which is afavorable prognostic marker at some tumor sites, whereas inother tumor sites, Treg infiltration may be associated with poorsurvival outcomes regarding their conventional regulatory function(13). The activation of Tregs may be associated with myeloidderived suppressor cells infiltration, these cells being associatedwith tumor progression and PD-L1 expression (14).LIMITATIONS AND HETEROGENEITYSTUDIESThe findings of studies investigating the immune cell features ofHPV-induced HNSCCs have to be considered with cautiousbecause many limitations. The method used to determine theHPV status may significantly vary from one to another study. Inmany centers, the detection of HPV infection is made with p16immunostaining. Some authors used p16 immunostaining tocompare data from HPV-positive and HPV-negative HNSCCs,while others used polymerase chain reaction (PCR) or otherFrontiers in Oncology | www.frontiersin.org 2direct methods of DNA identification (15). In fact, some tumorscan be HPV-positive/p16- or HPV-negative/p16+, which can berelated to the lack of specificity of p16 in identifying HPV infection.As demonstrated in two studies (15, 16), the use of p16immunostaining versus DNA detection may lead to substantialdifferences in the study results, which may bias the comparisonbetween studies.From an epidemiological standpoint, the analysis of studyresults (e.g. OS, disease-free survival) has to consider inclusioncriteria. For example, the survival analysis according to the HPVstratus has to consider the ethnicity, tumor site, tobacco andalcohol histories, and the types of treatment (e.g. surgery,chemoradiation, radiotherapy or immunotherapy) (15); all ofthese points being known to influence the immune cell infiltrate.PERSPECTIVES AND CONCLUSIONEpidemiological, clinical, and immunological outcomes of HPV-induced HNSCCs are all points investigated in studies of thisResearch Topic. Precisely, the following outcomes were studied inthe present Research Topic: prevalence data of HPV-inducedHNSCC in Syria (16), importance of extranodal extension HPV-positive OSCC (Gupta et al.), tumor microenvironment andimmunotherapy in OSCC (Beltz et al.), survival outcomesaccording to lymph node invasion in oral SCC (Welters et al.),nonsmoking and nondrinking outcomes in HNSCC (Li et al.;Yang et al.), the impact of tonsillectomy in the management ofunknown primary HNSCC regarding p16 status (Mulder et al.),and recurrent respiratory papillomatosis risk factors (Podeuret al.). Many grey areas have to be explored in the next fewyears to better understand the prognosis differences betweenHPV-positive and HPV-negative HNSCC patients, as well as theinfluence of some conditions on both immunological and survivalfeatures. A promising topic is the study of the influence of gut,laryngopharyngeal and oral microbiota on the immune regulationin tumor environment and its interaction with HPV infection.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct, and intellectualcontribution to the work and approved it for publication.ACKNOWLEDGMENTSAll reviewers who contributed to the reviewing process of thisResearch Topic.REFERENCES1. Global Burden of Disease Cancer Collaboration. Global, Regional, andNational Cancer Incidence, Mortality, Years of Life Lost, Years Lived WithDisability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to2017: A Systematic Analysis for the Global Burden of Disease Study. JAMAOncol (2019) 5:1749–68. doi: 10.1001/jamaoncol.2019.29962. Aupérin A. Epidemiology of Head and Neck Cancers: An Update. Curr OpinOncol (2020) 32(3):178–86. doi: 10.1097/CCO.00000000000006293. GillisonML, KochWM, Capone RB, SpaffordM,WestraWH,Wu L, et al. Evidencefor a Causal Association Between Human Papillomavirus and a Subset of Head andNeck Cancers. J Natl Cancer Inst (2000) 92(9):709–20. doi: 10.1093/jnci/92.9.7094. Filleul O, Preillon J, Crompot E, Lechien J, Saussez S. Incidence of Headand Neck Cancers in Belgium: Comparison With World Wide andMarch 2022 | Volume 12 | Article 795280Lechien et al. Editorial: HPV in Head & Neck CancerFrench Data. Bull Cancer (2011) 98(10):1173–83. doi: 10.1684/bdc.2011.14565. Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology ofHuman Papillomavirus-Positive Head and Neck Squamous Cell Carcinoma.J Clin Oncol (2015) 33:3235–42. doi: 10.1200/JCO.2015.61.69956. O’Rorke MA, Ellison MV, Murray LJ, Moran M, James J, Anderson LA.Human Papillomavirus Related Head and Neck Cancer Survival: ASystematic Review and Meta-Analysis. Oral Oncol (2012) 48(12):1191–201.doi: 10.1016/j.oraloncology.2012.06.0197. Descamps G, Karaca Y, Lechien JR, Kindt N, Decaestecker C, Remmelink M,et al. Classical Risk Factors, But Not HPV Status, Predict Survival AfterChemoradiotherapy in Advanced Head and Neck Cancer Patients. J CancerRes Clin Oncol (2016) 142(10):2185–96. doi: 10.1007/s00432-016-2203-78. Lechien JR, Seminerio I, Descamps G, Mat Q, Mouawad F, Hans S, et al.Impact of HPV Infection on the Immune System in Oropharyngeal and Non-Oropharyngeal Squamous Cell Carcinoma: A Systematic Review. Cells (2019)8(9):1061. doi: 10.3390/cells80910619. Russell S,AngellT, LechnerM,LiebertzDJ,CorreaAJ, SinhaUK, et al. ImmuneCellInfiltration Patterns and Survival in Head and Neck Squamous Cell Carcinoma.Head Neck Oncol (2013) 5(3):24.10. Partlová SM, Bouček JE, Kloudová KG, Lukesǒvá E, Zábrodský M, Grega M,et al. Distinct Patterns of Intratumoral Immune Cell Infiltrates in PatientsWith HPV-Associated Compared to Non-Virally Induced Head and NeckSquamous Cell Carcinoma. Oncoimmunology (2015) 4(1):e965570. doi:10.4161/21624011.2014.96557011. 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Cancer Immunol Immunother (2016) 65(4):393–403. doi: 10.1007/s00262–016–1805-xConflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2022 Lechien, Mouawad, Hans and Saussez. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License(CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and thatthe original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction is permitted which doesnot comply with these terms.March 2022 | Volume 12 | Article 795280

Editorial: Advances in the Involvement of Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma.

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Editorial: Advances in the Involvement of Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma.

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