The Eradication of Carcinogenic Viruses in Established Solid Cancers

Figures & data

Figure 1 A schematic presentation of the binary model for CD8+ T cell response to oncoviruses (and intracellular carcinogenic bacteria).

Figure 2 A decision tree regarding the eradication of oncoviruses (and intracellular carcinogenic bacteria) in established tumors.

Note: The model cannot be applied to certain lymphomas, to extracellular pathogens, and to pathogens which elicit host-sensitive immune response.

Table 1 Binary Classification of CD8+T Cell Reaction to Viral Infection of Benign Tissues, Eradication Recommendations, and Clinical Evidence Regarding the Effect of the Virus on Patients’ Prognosis

Oncovirus	Related Cancer(s)	CD8+ T Cell Reaction	References	Pathogen Eradication (the Binary Model)	Pathogen Eradication (Clinical Evidence or Practice)	References
HPV	Cervical cancer and head and neck cancer (mainly)	Strong	[12,25]	No	No	[47,48]
HBV	Hepatocellular carcinoma	Weak	[14,28–31]	Yes	Yes	[49–51]
HCV	Hepatocellular carcinoma	Weak	[15,32–34]	Yes	Yes	[52,53,55]
HHV-8	Kaposi’s sarcoma	Strong	[16,35]	No	No	[56]
HTLV1	Adult T-cell lymphoma/leukemia	Weak	[18,20,40,41]	Yes	Yes	[57,58]
EBV	Hodgkin lymphoma,	Strong	[13,19,42,43]	No	Yes (in elderly patients and in the largest study in children)	[59] (a review), [60]
EBV	Nasopharyngeal carcinoma	Strong	[13,19,42,43]	No	Yes	[61] (a pooled analysis)
MCPyV	Merkel cell carcinoma	Strong	[24,45,46]	No	No	[62]

Abbreviations: HPV, human papillomavirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV-8, human gamma herpesvirus 8; HTLV1, human T-cell lymphoma virus 1; EBV, Epstein-Barr virus; MCPyV, Merkel cell polyomavirus.

Çuburu N, Graham BS, Buck CB, et al. Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses. J Clin Invest. 2012;122(12):4606–4620. doi:10.1172/JCI63287

 PubMed Web of Science ®Google Scholar

Hibma MH. The immune response to papillomavirus during infection persistence and regression. Open Virol J. 2012;6:241–248. doi:10.2174/1874357901206010241

 PubMedGoogle Scholar

Lei J, Arroyo-Mühr LS, Lagheden C, et al. Human Papillomavirus Infection Determines Prognosis in Cervical Cancer. J Clin Oncol. 2022;40(14):1522–1528. doi:10.1200/JCO.21.01930

 PubMed Web of Science ®Google Scholar

Zhou P, Yu YF, Lian CL, Wang J, Zhuo RG, Wu SG. Survival Outcomes and Treatment Decision by Human Papillomavirus Status Among Patients With Stage IVC Head and Neck Squamous Cell Carcinoma. Front Oncol. 2021;11:668066. doi:10.3389/fonc.2021.668066

 PubMedGoogle Scholar

Boni C, Fisicaro P, Valdatta C, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol. 2007;81(8):4215–4225. doi:10.1128/JVI.02844-06

 PubMed Web of Science ®Google Scholar

Wieland D, Kemming J, Schuch A, et al. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. Nat Commun. 2017;8:15050. doi:10.1038/ncomms15050

 PubMed Web of Science ®Google Scholar

Yeh ML, Liang PC, Tsai PC, et al. Characteristics and Survival Outcomes of Hepatocellular Carcinoma Developed after HCV SVR. Cancers (Basel). 2021;13(14):3455. doi:10.3390/cancers13143455

 PubMed Web of Science ®Google Scholar

Luo Y, Zhang Y, Wang D, Shen D, Che YQ. Eradication of Hepatitis C Virus (HCV) Improves Survival of Hepatocellular Carcinoma Patients with Active HCV Infection - A Real-World Cohort Study. Cancer Manag Res. 2020;12:5323–5330. doi:10.2147/CMAR.S254580

 PubMed Web of Science ®Google Scholar

Muzica CM, Stanciu C, Huiban L, et al. Hepatocellular carcinoma after direct-acting antiviral hepatitis C virus therapy: a debate near the end. World J Gastroenterol. 2020;26(43):6770–6781. doi:10.3748/wjg.v26.i43.6770

 PubMed Web of Science ®Google Scholar

Lambert M, Gannagé M, Karras A, et al. Differences in the frequency and function of HHV8-specific CD8 T cells between asymptomatic HHV8 infection and Kaposi sarcoma. Blood. 2006;108(12):3871–3880. doi:10.1182/blood-2006-03-014225

 PubMed Web of Science ®Google Scholar

Lepone L, Rappocciolo G, Knowlton E, et al. Monofunctional and polyfunctional CD8+ T cell responses to human herpesvirus 8 lytic and latency proteins. Clin Vaccine Immunol. 2010;17(10):1507–1516. doi:10.1128/CVI.00189-10

 PubMedGoogle Scholar

Esser S, Schöfer H, Hoffmann C, et al. S1 Guidelines for the Kaposi Sarcoma. J Dtsch Dermatol Ges. 2022;20(6):892–904. doi:10.1111/ddg.14788

 Web of Science ®Google Scholar

Kozako T, Yoshimitsu M, Fujiwara H, et al. PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia. 2009;23(2):375–382. doi:10.1038/leu.2008.272

 PubMed Web of Science ®Google Scholar

Clements DM, Crumley B, Chew GM, et al. Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapeutic Strategies in HTLV-1 Infection. Front Immunol. 2021;12:608890. doi:10.3389/fimmu.2021.608890

 PubMed Web of Science ®Google Scholar

Espíndola OM, Siteur-van Rijnstra E, Frankin E, et al. Early Effects of HTLV-1 Infection on the Activation, Exhaustion, and Differentiation of T-Cells in Humanized NSG Mice. Cells. 2021;10(10):2514. doi:10.3390/cells10102514

 PubMed Web of Science ®Google Scholar

Hanon E, Stinchcombe JC, Saito M, et al. Fratricide among CD8(+) T lymphocytes naturally infected with human T cell lymphotropic virus type I. Immunity. 2000;13(5):657–664. doi:10.1016/s1074-7613(00)00065-0

 PubMed Web of Science ®Google Scholar

El Hajj H, Tsukasaki K, Cheminant M, Bazarbachi A, Watanabe T, Hermine O. Novel Treatments of Adult T Cell Leukemia Lymphoma. Front Microbiol. 2020;11:1062. doi:10.3389/fmicb.2020.01062

 PubMed Web of Science ®Google Scholar

Bazarbachi A, Plumelle Y, Carlos Ramos J, et al. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol. 2010;28(27):4177–4183. doi:10.1200/JCO.2010.28.0669

 PubMed Web of Science ®Google Scholar

Abbott RJ, Quinn LL, Leese AM, Scholes HM, Pachnio A, Rickinson AB. CD8+ T cell responses to lytic EBV infection: late antigen specificities as subdominant components of the total response. J Immunol. 2013;191(11):5398–5409. doi:10.4049/jimmunol.1301629

 PubMed Web of Science ®Google Scholar

Chatterjee B, Deng Y, Holler A, et al. CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo. PLoS Pathog. 2019;15(5):e1007748. doi:10.1371/journal.ppat.1007748

 PubMed Web of Science ®Google Scholar

Maini MK, Gudgeon N, Wedderburn LR, Rickinson AB, Beverley PC. Clonal expansions in acute EBV infection are detectable in the CD8 and not the CD4 subset and persist with a variable CD45 phenotype. J Immunol. 2000;165(10):5729–5737. doi:10.4049/jimmunol.165.10.5729

 PubMed Web of Science ®Google Scholar

Callan MF, Tan L, Annels N, et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo. J Exp Med. 1998;187(9):1395–1402. doi:10.1084/jem.187.9.1395

 PubMed Web of Science ®Google Scholar

Nohtani M, Vrzalikova K, Ibrahim M, et al. Impact of Tumour Epstein--Barr Virus Status on Clinical Outcome in Patients with Classical Hodgkin Lymphoma (cHL): a Review of the Literature and Analysis of a Clinical Trial Cohort of Children with cHL. Cancers (Basel). 2022;14(17):4297. doi:10.3390/cancers14174297

 PubMed Web of Science ®Google Scholar

Claviez A, Tiemann M, Lüders H, et al. Impact of latent Epstein--Barr virus infection on outcome in children and adolescents with Hodgkin’s lymphoma. J Clin Oncol. 2005;23(18):4048–4056. doi:10.1200/JCO.2005.01.701

 PubMed Web of Science ®Google Scholar

Alami IE, Gihbid A, Charoute H, et al. Prognostic value of Epstein--Barr virus DNA load in nasopharyngeal carcinoma: a meta-analysis. Pan Afr Med J. 2022;41:6. doi:10.11604/pamj.2022.41.6.28946

 PubMed Web of Science ®Google Scholar

Ganusov VV, Lukacher AE, Byers AM. Persistence of viral infection despite similar killing efficacy of antiviral CD8(+) T cells during acute and chronic phases of infection. Virology. 2010;405(1):193–200. doi:10.1016/j.virol.2010.05.029

 PubMed Web of Science ®Google Scholar

Wilson JJ, Pack CD, Lin E, et al. CD8 T cells recruited early in mouse polyomavirus infection undergo exhaustion. J Immunol. 2012;188(9):4340–4348. doi:10.4049/jimmunol.1103727

 PubMed Web of Science ®Google Scholar

Vezys V, Masopust D, Kemball CC, et al. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J Exp Med. 2006;203(10):2263–2269. doi:10.1084/jem.20060995

 PubMed Web of Science ®Google Scholar

Yang A, Wijaya WA, Lie Y, et al. The impact of Merkel Cell polyomavirus positivity on prognosis of Merkel cell carcinoma: a systematic review and meta-analysis. Front Oncol. 2022. doi:10.3389/fonc.2022.1020805

 Web of Science ®Google Scholar