Preclinical models of HPV+ and HPV− HNSCC in mice: An immune clearance of HPV+ HNSCC

Williams, Robin L.; Lee, Dong Hoon; Elzey, Bennett D.; Anderson, Mary E.; Hostager, Bruce S.; Lee, John H.

doi:10.1002/hed.21040

Cited by 96 publications

(101 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…HPV-related xenografts grow more quickly in Rag 1 immune-compromised than in wild-type mice. 30 Cisplatinbased therapy results in tumor clearance in wild type but not in Rag 1 mice. 31 Two studies have shown that the proportion of T cells that are specific for HPV16 E7 peptides among CD8þ T cell is significantly increased (three to fourfold) in PBMC of patients with HPV-positive oropharyngeal cancer when compared with HPV-negative patients.…”

Section: Discussionmentioning

confidence: 99%

CD8‐alpha T‐cell infiltration in human papillomavirus‐related oropharyngeal carcinoma correlates with improved patient prognosis

Jung

Guihard²,

Krugell³

et al. 2012

Intl Journal of Cancer

View full text Add to dashboard Cite

Patients with human papillomavirus (HPV)-related oropharyngeal tumors display improved prognosis. The biological basis of this tumor phenotype is poorly understood. We investigated whether increased lymphocyte infiltrate in HPV-positive oropharyngeal squamous cell carcinomas could account for better prognosis. We previously identified, in an Affymetrix GeneChip analysis of 83 HPV-unrelated and 11 HPV-related squamous cell carcinoma of the oropharynx, several candidate genes, including CD8a and CD3f. Their expression was validated in this study by qRT-PCR on an independent clinical series of 144 oropharyngeal tumors. Immunohistochemical staining of tumor specimens was performed to evaluate infiltration of tumor stroma by CD81 and CD41 lymphocytes. The prognostic value of CD8a and CD3f expression levels was measured by Kaplan-Meier and Cox regression model analyses. Immune response-related signaling pathways were found to be deregulated in HPV-positive oropharyngeal tumors. Expression of CD8a, CD3f, granzyme K, CD28 and integrin aL RNAs was upregulated in HPV-positive lesions when compared with HPV-unrelated tumors (p < 0.05). Stroma of HPV-positive tumors was frequently and strongly infiltrated by CD8a-and CD3f-positive T cells. CD8a RNA expression correlated with both improved global (Kaplan-Meier; p 5 0.005; Cox regression: p 5 0.003) and disease-free (Cox regression: p 5 0.04) survival. CD3f RNA expression correlated with improved overall survival (Cox regression: p 5 0.024). These results suggest that an increased cytotoxic T-cell-based antitumor immune response is involved in improved prognosis of patients with HPV-positive tumors.The presence of human papillomaviruses (HPVs; mainly HPV type 16) correlates with the onset and development of about 25% of head and neck squamous cell carcinomas (HNSCC). 1 HPV-positive cancers of the head and neck arise mainly in the oropharynx and define a subgroup of radioand chemosensitive tumors with distinct clinical, pathological and molecular features and improved prognosis with respect to their HPV-negative counterparts. [2][3][4][5] The majority of HPVrelated oropharyngeal squamous cell carcinomas (OSCC) express wild-type TP53, 6,7 which might be involved in the improved response of tumors to treatment. Despite thorough analysis of gene expression profiles of HPV-positive OSCC by several groups, [8][9][10][11] no novel prognostic or predictive biomarker has been identified, and the molecular mechanisms that underlie improved prognosis of HPV-related OSCC are poorly understood.The immune response has an important impact in many HPV-associated tumors and can have either favorable or unfavorable consequences. 12 The importance of the immune response in HPV-related OSCC is less well established. An increased T-cell response against HPV E7 epitopes has been detected in the blood of patients with HPV-positive HNSCC. 13-15 A more recent study has shown that T cells that proliferate and synthesize inflammatory cytokines upon HPV16 E6 and E7 oncoprotein recognition can be isolate...

show abstract

Section: Discussionmentioning

confidence: 99%

CD8‐alpha T‐cell infiltration in human papillomavirus‐related oropharyngeal carcinoma correlates with improved patient prognosis

Jung

Guihard²,

Krugell³

et al. 2012

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…In this model, the tumor cells are not controlled by tumor immunity, and mice implanted with MTECs develop tumors and die (16). The administration of CD137 agonist therapy led to the delay in tumor growth compared with nontreated animals (data not shown).…”

Section: Cd137 Signaling Elicits Activation Proliferation and Diffementioning

confidence: 93%

“…Mouse epithelial cells (MTECs) are transformed mouse tonsil epithelial cells, which do not carry viral proteins (HPV 2 ) (16). MTECs were grown in E media containing DMEM as previously described (16).…”

Section: Cell Linesmentioning

confidence: 99%

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus–induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4+ T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8+ T cell–deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4+ T cells. Interestingly, a subset of CD4+Foxp3+ regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4+ T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3+CD4+ T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.

show abstract

“…Viral persistence followed by HR-HPV infection, particularly HPV-16 and 18, is a crucial risk factor for carcinogenesis [83]. Besides the effect of viral oncogenes E6/7, many reports have indicated that HPV infection could change the status of the host immune system [84]. Patients with HPV-positive HNSCC tend to be younger and have a lower intake of tobacco and alcohol.…”

Section: Mirna Profile Of Hpv-related Oral Cancersmentioning

confidence: 99%

Effect of HPV status, smoking and alcohol consumption, on miRNA expression in oral cancer - a review of the literature

Tonchev¹,

Vladimirov²,

Sarafian³

et al. 2017

Int J Surg Med

View full text Add to dashboard Cite

Oral squamous cell carcinoma (OSCC) is the most common cancer type arising in the oral cavity and belongs to the wider group of head and neck cancers (HNCs).MicroRNAs (miRNAs) in mature form are noncoding RNAs, that regulate posttranscriptional gene expression by relatively nonspecific binding.As a result a single miRNA may regulate/control the expression of several genes which are involved in a variety of cellular processes like regulation of cellular differentiation, proliferation and apoptosis thus playing a role in cancer development.The AIM of this review was to summarize current findings on the effect of HPV status and presence of risk factors -smoking and alcohol consumption on miRNA expression as cancer biomarkers in patients with OSCC.

show abstract

Preclinical models of HPV+ and HPV− HNSCC in mice: An immune clearance of HPV+ HNSCC

Abstract: The findings from this preclinical model will have implications not only in understanding human disease but also as a valuable model for testing immunotherapeutic strategies for HPV+ head and neck cancer.

Cited by 96 publications

References 48 publications

CD8‐alpha T‐cell infiltration in human papillomavirus‐related oropharyngeal carcinoma correlates with improved patient prognosis

CD8‐alpha T‐cell infiltration in human papillomavirus‐related oropharyngeal carcinoma correlates with improved patient prognosis

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Effect of HPV status, smoking and alcohol consumption, on miRNA expression in oral cancer - a review of the literature

Contact Info

Product

Resources

About