Biomedical subjects

Robert L Ferris

Publications and source records attributed to Robert L Ferris.

At least 19 recordsLinked to original sources

PubMed2007

Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling.

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease that has been linked to altered immune, inflammatory, and angiogenesis responses. A better understanding of these aberrant responses might improve early detection and prognosis of SCCHN and provide novel therapeutic targets. Previous studies examined the role of multiplexed serum biomarkers in small cohorts or SCCHN sera. We hypothesized that an expanded panel comprised of multiple cytokines, chemokines, growth factors, and other tumor markers, which individually may show some promising correlation with disease status, might provide higher diagnostic power if used in combination. Thus, we evaluated a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple serum biomarkers. Concentrations of 60 cytokines, growth factors, and tumor antigens were measured in the sera of 116 SCCHN patients before treatment (active disease group), 103 patients who were successfully treated (no evidence of disease group), and 117 smoker controls without evidence of cancer. The multimarker panel offering the highest diagnostic power was comprised of 25 biomarkers, including epidermal growth factor, epidermal growth factor receptor, interleukin (IL)-8, tissue plasminogen activator inhibitor-1, alpha-fetoprotein, matrix metalloproteinase-2, matrix metalloproteinase-3, IFN-alpha, IFN-gamma, IFN-inducible protein-10, regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein-1alpha, IL-7, IL-17, IL-1 receptor-alpha, IL-2 receptor, granulocyte colony-stimulating factor, mesothelin, insulin-like growth factor binding protein 1, E-selectin, cytokeratin-19, vascular cell adhesion molecule, and cancer antigen-125. Statistical analysis using an ADE algorithm resulted in a sensitivity of 84.5%, specificity of 98%, and 92% of patients in the active disease group correctly classified from a cross-validation serum set. The data presented show that simultaneous testing using a multiplexed panel of serum biomarkers may present a promising new approach for the early detection of head and neck cancer.

Adult↗

PubMed2006

Identification of differentially expressed genes in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas.

Human papillomaviruses (HPVs) have been implicated in the pathogenesis of a subset of squamous cell carcinoma of the head and neck (SCCHN). The goal of this study was to compare the cellular gene expression profiles of HPV-positive and HPV-negative oropharyngeal carcinomas with those of the normal oral epithelium. Using Affymetrix Human U133A GeneChip, our results showed that 397 genes were differentially expressed in HPV-positive SCCHN compared to the normal oral epithelium. The upregulated genes included those involved in cell cycle regulation (CDKN2A), cell differentiation (SFRP4) and DNA repair (RAD51AP1), while the downregulated genes included those involved in proteolysis (PRSS3). We also found 162 differentially expressed genes in HPV-negative SCCHN compared to the normal oral mucosa. The upregulated genes included those involved in cell proliferation (AKR1C3) and transcription regulation (SNAPC1), while downregulated genes included those involved in apoptosis (CLU) and RNA processing (RBM3). Our studies also identified a subgroup of 59 differentially expressed genes in HPV-positive SCCHN as compared to both HPV-negative SCCHN and normal oral tissues. Such upregulated genes included those involved in nuclear structure and meiosis (SYCP2), DNA repair (RFC5), and transcription regulation (ZNF238). Genes involved in proteolysis (KLK8) and signal transduction (CRABP2) were found to be downregulated in HPV-positive SCCHN. The results of GeneChip experiments were validated by quantitative real-time RT-PCR analysis of a few representative genes. Our results reveal specific gene expression patterns in HPV-positive and HPV-negative oropharyngeal squamous carcinomas that may serve as potential biomarkers for the development of SCCHN.

Carcinoma, Squamous Cell↗

PubMed2006

Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer.

Recent revival of interest in the role of immune surveillance in the pathogenesis and control of malignant diseases has focused attention on escape mechanisms used by tumor cells to evade immune recognition. Defects in the host's tumor antigen-specific immune responses and abnormalities in tumor cell expression of HLA class I molecules and tumor antigen are known to contribute to tumor progression. However, the mechanism(s) responsible for the lack of tumor cell recognition by functional HLA class I antigen-restricted, tumor antigen-specific CTLs despite expression of the restricting HLA class I allele and targeted tumor antigen by tumor cells remain(s) unexplained. In squamous cell carcinomas of the head and neck (SCCHN), this type of tumor escape is a rule rather than the exception. Here, we discuss evidence pointing to functional defects in the antigen-processing machinery as one mechanism underlying resistance of SCCHN cells to recognition and lysis by HLA class I antigen-restricted, tumor antigen-specific CTL. In addition, based on the restoration by IFN-gamma of SCCHN cell sensitivity to recognition by these CTL, we suggest strategies that may improve the clinical course of the disease by enhancing susceptibility of malignant cells to immune recognition.

Antigen Presentation↗

PubMed2006

Posttreatment assessment of response using FDG-PET/CT for patients treated with definitive radiation therapy for head and neck cancers.

PURPOSE: The goal of this study was to evaluate coregistered [18F] fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) for the detection of persistent disease after definitive radiation therapy in head and neck cancer. METHODS AND MATERIALS: Posttreatment FDG-PET/CT was performed in 28 patients on average 8 weeks (range, 4 to 15.7 weeks) after completing definitive radiation therapy. FDG-PET/CT was visually analyzed for the entire patient group and at two time points (4-8 and >8 weeks) after treatment. The contrast-enhanced CT portion of PET/CT was separately analyzed blinded to the results of coregistered FDG-PET/CT and classified as negative or positive for residual locoregional disease. Pathologic findings and clinical follow-up served as the reference standard. RESULTS: Follow-up data were available for all 28 patients (median, 17.6 months). Regarding the detection of residual disease, the overall sensitivity and specificity of FDG-PET/CT was 76.9% and 93.3%, respectively, compared with 92.3% and 46.7% for contrast-enhanced CT. The accuracy of FDG-PET/CT was 85.7%, compared with 67.9% for CT alone. All false-negative (n = 3) and false-positive (n = 1) FDG-PET/CT results occurred between 4 and 8 weeks after treatment. At 8 weeks or later after treatment, the specificity of CT was 28%, compared with 100% for FDG-PET/CT. CONCLUSIONS: The metabolic-anatomic information from coregistered FDG-PET/CT provided the most accurate assessment for treatment response when performed later than 8 weeks after the conclusion of radiation therapy. FDG-PET/CT excelled by a higher specificity and overall diagnostic performance than CT imaging alone. These results support a potential clinical role of FDG-PET/CT in the early assessment of therapy response after definitive radiation therapy.

Adult↗

PubMed2006

Alterations in the T-cell receptor variable beta gene-restricted profile of CD8+ T lymphocytes in the peripheral circulation of patients with squamous cell carcinoma of the head and neck.

PURPOSE: Apoptosis of activated CD8(+) T cells is often seen in tumor-infiltrating lymphocytes and circulating peripheral blood mononuclear cells (PBMC) in patients with squamous cell carcinoma of the head and neck (SCCHN). We investigated whether T-cell receptor (TCR) variable beta chain (Vbeta)-restricted T cells were more sensitive to apoptosis than non-TCR Vbeta-restricted T cells. EXPERIMENTAL DESIGN: Flow cytometry analysis with anti-TCR Vbeta antibodies was used to define expansions and contractions of Vbeta-restricted T cells in patients with SCCHN relative to normal donors. This staining was combined with Annexin V binding to indicate early T-cell apoptosis. RESULTS: The TCR Vbeta profiles of CD3(+) T cells in tumor-infiltrating lymphocytes and PBMCs of patients with SCCHN were altered relative to controls, with one to five expansions and numerous contractions of TCR Vbeta-restricted T cells detected. These types of alterations were significantly greater in CD8(+) than CD4(+) T cells. Enhanced Annexin V binding to CD8(+) T cells was evident in PBMCs obtained from all patients, with 3 of 13 showing preferential targeting for apoptosis of TCR Vbeta-restricted T cells. CONCLUSIONS: TCR Vbeta profiles of CD8(+) T cells were altered in patients with SCCHN relative to normal controls. This may reflect increased apoptosis of expanded or contracted CD8(+) T cells, which define the TCR Vbeta profile of antigen-responsive T-cell populations in patients with cancer.

CD3 Complex↗

PubMed2006

Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL.

Squamous cell carcinoma of the head and neck (SCCHN) cells are poorly recognized in vitro by CTL despite expressing the restricting HLA class I allele and the targeted tumor Ag (TA). Several lines of evidence indicate that the lack of SCCHN cell recognition by CTL reflects defects in targeted TA peptide presentation by HLA class I Ag to CTL because of Ag-processing machinery (APM) dysfunction. First, lack of recognition of SCCHN cells by CTL is associated with marked down-regulation of the IFN-gamma-inducible APM components low-m.w. protein 2, TAP1, TAP2, and tapasin. Second, SCCHN cell recognition by CTL is restored by pulsing cells with exogenous targeted TA peptide. Third, the restoration of CTL recognition following incubation of SCCHN cells with IFN-gamma is associated with a significant (p = 0.001) up-regulation of the APM components TAP1, TAP2, and tapasin. Lastly, and most conclusively, SCCHN cell recognition by CTL is restored by transfection with wild-type TAP1 cDNA. Our findings may explain the association between APM component down-regulation and poor clinical course of the disease in SCCHN. Furthermore, the regulatory nature of the APM defects in SCCHN cells suggests that intralesional administration of IFN-gamma may have a beneficial effect on the clinical course of the disease and on T cell-based immunotherapy of SCCHN by restoring SCCHN cell recognition by CTL.

Antigen Presentation↗

PubMed2006

Prognosis as a determinant of free flap utilization for reconstruction of the lateral mandibular defect.

BACKGROUND: The purpose of this study was to determine whether patients with a poor prognosis for survival were more likely to undergo reconstruction with a pectoralis flap versus a free flap and whether the use of a pectoralis flap offered any perioperative advantage, such as a reduction in medical complications. METHODS: Fifty-five consecutive patients who underwent immediate reconstruction after a lateral mandibulectomy were retrospectively reviewed. RESULTS: Age >or=70 years (p = .03), moderate or severe comorbidity (p = .02), and involvement of the base of tongue by tumor (p = .04) were significantly associated with decreased utilization of a free flap (n = 36). Comorbidity was the main determinant of medical complications (p = .001) and length of hospital stay (p = .03). CONCLUSIONS: Expectations of prognosis bias the surgeon's decision regarding flap selection. Reconstruction with a pectoralis flap does not necessarily contribute toward the desired outcome of reduced medical complications. Any functional comparison between reconstructive groups needs to account for those differences in health status and prognosis that might explain any observed postoperative differences.

Age Factors↗

PubMed2006

Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies?

The tumor microenvironment consists of a variable combination of tumor cells, stromal fibroblasts, endothelial cells and infiltrating leukocytes, such as macrophages, T lymphocytes, and dendritic cells. A variety of cytokines, chemokines and growth factors are produced in the local tumor environment by different cells accounting for a complex cell interaction and regulation of differentiation, activation, function and survival of multiple cell types. The interaction between cytokines, chemokines, growth factors and their receptors forms a comprehensive network at the tumor site, which is primary responsible for overall tumor progression and spreading or induction of antitumor immune responses and tumor rejection. Although the general thought is that dendritic cells are among the first cells migrating to the tumor site and recognizing tumor cells for the induction of specific antitumor immunity, the clinical relevance of dendritic cells at the site of the tumor remains a matter of debate regarding their role in the generation of successful antitumor immune responses in human cancers. While several lines of evidence suggest that intratumoral dendritic cells play an important role in antitumor immune responses, understanding the mechanisms of dendritic cell/tumor cell interaction and modulation of activity and function of different dendritic cell subtypes at the tumor site is incomplete. This review is limited to discussing the role of intratumoral cytokine network in the understanding immunobiology of tumor-associated dendritic cells, which seems to possess different regulatory functions at the tumor site.

Chemokines↗

PubMed2005

Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck.

Human papillomavirus (HPV)-associated squamous cell carcinoma of the head and neck (SCCHN) seems to be a suitable target for cancer vaccination. HPV-encoded oncogenic proteins, such as E7, are promising tumor-specific antigens and are obligatory for tumor growth. Because few immunologic studies have analyzed the endogenous HPV-specific immune response in this subset of SCCHN patients, we studied T-cell frequencies against HPV-16 E7(11-20) or E7(86-93) in tumor-bearing, human leukocyte antigen (HLA)-A*0201+ SCCHN patients, whose tumors were either HPV-16+ or HPV-16-. In HPV-16+ SCCHN patients, frequencies of T cells against either peptide were significantly elevated (P < 0.005) compared with HPV-16- patients or healthy volunteers. Tetramer+ T cells showed evidence of terminally differentiated phenotype (CD45RA+CCR7-) and an elevated level of CD107a staining for degranulation. Despite detectable expression of the restricting HLA class I allele, HLA-A*0201-E7(11-20)- or HLA-A*0201-E7(86-93)-specific CTL obtained by in vitro stimulation of healthy donor peripheral blood mononuclear cells only recognize a naturally HPV-16-transformed, HLA-A*0201+ SCCHN cell line after pretreatment with IFN-gamma. This cell line had little or no expression of LMP2, TAP1, and tapasin, critical components of the HLA class I antigen-processing machinery, which were up-regulated by IFN-gamma treatment. Immunohistochemistry of HPV-16+ SCCHN tumors showed that these antigen-processing machinery components are down-regulated in tumors in vivo compared with adjacent normal squamous epithelium. Thus, immunity to HPV-16 E7 is associated with the presence of HPV-16 infection and presentation of E7-derived peptides on SCCHN cells, which show evidence of immune escape. These findings support further development of E7-specific immunotherapy and strategies for up-regulation of antigen-processing machinery components in HPV-associated SCCHN.

Animals↗

PubMed2005

Chemokine C receptor 7 expression and protection of circulating CD8+ T lymphocytes from apoptosis.

Chemokine C receptor 7 (CCR7) expression is important for lymphocyte homing to tissues. We hypothesized that CCR7 also plays a role in CD8(+) T-cell protection from apoptosis. Its expression was determined on circulating T cells in patients with cancer and related to that of molecules responsible for lymphocyte susceptibility/resistance to apoptosis. Peripheral blood mononuclear cells were obtained from 36 patients with squamous cell carcinoma of the head and neck and 16 normal controls. Multicolor flow cytometry was used to evaluate CCR7, Fas, Bax, and Bcl-2 expression in CD8(+) T cells. Annexin V binding to CD8(+)CCR7(+) and CD8(+)CCR7(-) T-cell subsets was compared. Fewer CD8(+)CCR7(+) T cells bound Annexin V than CD8(+)CCR7(-) T cells in normal control and patients (P < 0.0001). CCR7 expression correlated with higher Bcl-2 but lower Bax and Fas expression levels in CD8(+) T cells in both normal control and patients (P < 0.0001). In patients, the CD8(+)CCR7(+) subset was reduced relative to normal control (P = 0.008) and replaced with an excess of apoptosis-sensitive CD8(+)CCR7(-) T cells. To study CCR7 signaling, CD8(+) T cells were stimulated with CCR7 ligands, chemokine C ligands 19 or 21. Ligand binding to CCR7 resulted in phosphorylation of Akt and increased Bcl-2 expression in CD8(+)CCR7(+) T cells, suggesting that CCR7 protects effector T cells from apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. The absence of CCR7 expression on the majority of CD8(+) T cells in the peripheral circulation of patients with squamous cell carcinoma of the head and neck contributes to apoptosis and a rapid turnover of these effector cells.

Annexin A5↗

PubMed2005

Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR.

Chemokine receptor 7 (CCR7) upregulation, which mediates immune cell survival and migration to lymph nodes, has recently been associated with nodal metastasis of squamous cell carcinoma of the head and neck (SCCHN). However, the mechanism of CCR7 in tumor progression, its downstream signaling mediators, and interactions with other pathways contributing to metastasis of SCCHN have not been determined. We hypothesized that inflammatory chemokine-mediated signals could also promote tumor proliferation and mitogenic effects. Functional assays showed that chemotaxis and invasion of metastatic SCCHN cells were dependent on phosphoinositide-3 kinase (PI3K) and its substrate, activated phospholipase Cgamma-1. In addition, treatment of CCR7(+) metastatic SCCHN cells with CCL19 (MIP-3beta) showed rapid activation of the prosurvival, PI3K/Akt pathway. Transactivation of EGFR-mediated and mitogen-activated protein kinase signaling pathways, which can promote migration and survival in parallel, did not appear to contribute to the functional or biochemical effects of CCR7 stimulation. Thus, proinflammatory chemokine signals that mediate activation, trafficking and survival of tumor-infiltrating immune cells in the tumor microenvironment actually appear to induce signals for progression of cancer cells. The CCR7-mediated pathway in metastatic SCCHN cells functions independently of EGFR signal transduction and therefore may represent an additional target for therapeutic intervention to prevent tumor progression and metastasis.

1-Phosphatidylinositol 4-Kinase↗

PubMed2005

Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma.

Originally characterized as a growth factor for erythrocytes, erythropoietin (EPO) is used to treat anemia and fatigue in cancer patients receiving radiation therapy and chemotherapy. EPO and the EPO receptor (EPOR) are expressed in nonhematopoietic cells and cancers. However, the role of EPO and EPOR within nonhematopoietic cancer cells remains incompletely understood. Although a recent clinical trial demonstrated worse tumor control and survival in head and neck cancer patients treated with EPO, the role of EPO and EPOR in head and neck squamous cell carcinoma (HNSCC) has not been examined. In the present study, we demonstrate the previously unrecognized EPO-mediated invasion by HNSCC cells through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Furthermore, we confirmed the expression of EPO and EPOR in a panel of human HNSCC cell lines and tissue specimens. Pharmacological doses of EPO also had a limited proliferation effect in these cell lines. These results define a novel role for EPO in mediating tumor cell invasion. Increased levels of EPO and EPOR in lymph node metastases as compared to primary tumors from HNSCC patients further support the role of EPO/EPOR in HNSCC disease progression and metastasis.

Aged↗

PubMed2005

Immune responses to p53 in patients with cancer: enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites.

OBJECTIVE: A majority of human cancers, including head and neck cancer (HNC), "overexpress" p53. Although T cells specific for wild-type (wt) sequence p53 peptides are detectable in the peripheral blood of patients with HNC, it is unknown whether such T cells accumulate in tumor-involved tissues. Also, the localization of "regulatory" T cells (Treg) to tumor sites in HNC has not been investigated to date. METHODS: Tumor infiltrating lymphocytes (TIL), tumor-involved or non-involved lymph node lymphocytes (LNL) and peripheral blood mononuclear cells (PBMC) were obtained from 24 HLA-A2.1+ patients with HNC. Using tetramers and four-color flow cytometry, the frequency of Treg and CD3+CD8+ T cells specific for wt p53 epitopes as well as their functional attributes were determined. RESULTS: The CD3+CD8+ tetramer+ cell frequency was significantly higher (P<0.001) in TIL than autologous PBMC as was the percentage of CD4+CD25+ T cells (P<0.003). TIL were enriched in FOXp3+, GITR+ and CTLA-4+ Treg. CD8+ TIL had low Zeta expression and produced little IFN-gamma after ex vivo stimulation relative to autologous PBMC or PBMC from NC. CONCLUSIONS: Anti-wt p53 epitope-specific T cells and Treg preferentially localize to tumor sites in patients with HNC. However, despite enrichment in tumor peptide-specific T cells, the effector cell population (CD3+CD8+) in TIL or PBMC was unresponsive to activation in the tumor microenvironment enriched in Treg.

Adult↗

PubMed2005

Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo.

Breast and kidney-expressed chemokine (BRAK) CXCL14 is a new CXC chemokine with unknown function and receptor selectivity. The majority of head and neck squamous cell carcinoma (HNSCC) and some cervical squamous cell carcinoma do not express CXCL14 mRNA, as opposed to constitutive expression by normal oral squamous epithelium. In this study, we demonstrate that the loss of CXCL14 in HNSCC cells and at HNSCC primary tumor sites was correlated with low or no attraction of dendritic cell (DC) in vitro, and decreased infiltration of HNSCC mass by DC at the tumor site in vivo. Next, we found that recombinant human CXCL14 and CXCL14-positive HNSCC cell lines induced DC attraction in vitro, whereas CXCL14-negative HNSCC cells did not chemoattract DC. Transduction of CXCL14-negative HNSCC cell lines with the human CXCL14 gene resulted in stimulation of DC attraction in vitro and increased tumor infiltration by DC in vivo in chimeric animal models. Furthermore, evaluating the biologic effect of CXCL14 on DC, we demonstrated that the addition of recombinant human CXCL14 to DC cultures resulted in up-regulation of the expression of DC maturation markers, as well as enhanced proliferation of allogeneic T cells in MLR. Activation of DC with recombinant human CXCL14 was accompanied by up-regulation of NF-kappaB activity. These data suggest that CXCL14 is a potent chemoattractant and activator of DC and might be involved in DC homing in vivo.

Animals↗

PubMed2005

Molecular staging of cervical lymph nodes in squamous cell carcinoma of the head and neck.

Clinical staging of cervical lymph nodes from patients with squamous cell carcinoma of the head and neck (SCCHN) has only 50% accuracy compared with definitive pathologic assessment. Consequently, both clinically positive and clinically negative patients frequently undergo neck dissections that may not be necessary. To address this potential overtreatment, sentinel lymph node (SLN) biopsy is currently being evaluated to provide better staging of the neck. However, to fully realize the potential improvement in patient care afforded by the SLN procedure, a rapid and accurate SLN analysis is necessary. We used quantitative reverse transcription-PCR (QRT-PCR) to screen 40 potential markers for their ability to detect SCCHN metastases to cervical lymph nodes. Seven markers were identified with good characteristics for identifying metastatic disease, and these were validated using a set of 26 primary tumors, 19 histologically positive lymph nodes, and 21 benign nodes from patients without cancer. Four markers discriminated between positive and benign nodes with accuracy >97% but only one marker, pemphigus vulgaris antigen (PVA), discriminated with 100% accuracy in both the observed data and a statistical bootstrap analysis. A rapid QRT-PCR assay for PVA was then developed and incorporated into a prototype instrument capable of performing fully automated RNA isolation and QRT-PCR. The automated analysis with PVA provided perfect discrimination between histologically positive and benign lymph nodes and correctly identified two lymph nodes with micrometastatic tumor deposits. These assays were completed (from tissue to result) in approximately 30 minutes, thus demonstrating the feasibility of intraoperative staging of SCCHN SLNs by QRT-PCR.

Adult↗

PubMed2005

Recent thymic emigrants and subsets of naive and memory T cells in the circulation of patients with head and neck cancer.

Apoptosis of circulating CD8+ T lymphocytes is a frequent finding in patients with cancer. T-cell output by the thymus or antigen-driven expansion of circulating T cells could compensate for apoptosis and thus normalize their homeostasis. We studied the frequency of recent thymic emigrants (RTE) identified by T-cell receptor excision circles (TREC) and of naive and memory T-cell subsets in peripheral blood samples obtained from 39 patients with head and neck cancer (HNC) and 33 age-matched controls (NC). TREC numbers were determined by real-time quantitative PCR, and CD8+CD45RO-CD27+ or CD4+CD45RO-CD27+ T-cell subsets were quantified by flow cytometry. Age-associated decreases in TREC numbers and proportions of naive CD8+ and CD4+ T-cell subsets were significantly greater in cancer patients than NC. In contrast, the memory compartment was expanded, with increased proportions of CD4+CD45RO+ but not CD8+CD45RO+ T cells, in cancer patients vs. NC. These alterations did not normalize in patients who were NED. The data suggest that lower thymic output combined with rapid turnover of naive CD8+ T cells account for altered lymphocyte homeostasis in HNC patients. The defect persists long after curative treatments and may contribute to immune cell dysregulation in patients with cancer.

Adult↗

PubMed2005

Human papillomavirus-16 associated squamous cell carcinoma of the head and neck (SCCHN): a natural disease model provides insights into viral carcinogenesis.

Uncertainty regarding the causality of human papillomaviruses (HPVs) in squamous cell carcinoma of the head and neck (SCCHN) necessitates better in vitro models. We carried out molecular analyses of a novel, naturally HPV-16-transformed SCCHN cell line (UPCI:SCC090) and show high copy number of HPV-16 DNA, present in a head to tail, tandemly repeated integrated state. Sequence analysis of the HPV-16 long control region (LCR) in UPCI:SCC090 revealed a deletion of 163 bp, removing a portion of the enhancer sequence, including the binding sites for the transcription factors YY1 and NF1. The E6 and E7 oncogenes of HPV-16 are expressed at high levels in this cell lines, as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). UPCI:SCC090 contains wild-type tumour suppressor TP53 gene, and undetectable p53 protein, except after treatment with cisplatin, specific proteasome inhibitors or by E6 RNA interference, suggesting E6-dependent degradation of p53 in this cell line. The results of our studies are consistent with a causative role of HPV-16 in the pathogenesis of SCCHN.

Blotting, Southern↗

PubMed2005

Antiviral activity of Cidofovir on a naturally human papillomavirus-16 infected squamous cell carcinoma of the head and neck (SCCHN) cell line improves radiation sensitivity.

High risk HPV types 16 and 18 are associated with cervical cancer and squamous cell carcinoma of the head and neck (SCCHN). Cidofovir is an antiviral drug used to treat HPV-induced laryngeal papillomatosis and other viral infections, with initial reports suggesting activity in cervical carcinoma cells. We investigated the effects of Cidofovir on a naturally HPV-16-transformed SCCHN cell line (UPCI:SCC090), in comparison with a cervical carcinoma cell line (CasKi) of similar viral characteristics, to evaluate its therapeutic potential. HPV-16 gene transcription was only marginally reduced, and the antiviral and p53 restorative effects were modest in SCC90 cells. However, combination with irradiation enhanced the effects of Cidofovir treatment on these cells. Several days of treatment were required for this effect, which may limit its clinical applicability. Future therapies for HPV-associated tumors may include intralesional antiviral therapy in combination with radiation therapy, but optimization for clinical utility is needed.

Adult↗