BackgroundHuman Leukocyte Antigen (HLA)-E is a non-classical class I HLA molecule that can be stabilized by ligands donated by other classical (HLA-A, -B, -C) and non-classical (HLA-G) family members. HLA-E engages a variety of immune receptors expressed by cytotoxic T lymphocytes (CTLs), Natural killer (NK) cells and NK-CTLs. In view of the opposing outcomes (activation or inhibition) of the different HLA-E receptors, the preferred role (if any) of HLA-E expressed in vivo on tumor cells remains to be established.MethodsTaking advantage of MEM-E/02, a recently characterized antibody to denatured HLA-E molecules, HLA-E expression was assessed by immunohistochemistry on an archival collection (formalin-fixed paraffin-embedded) of 149 colorectal primary carcinoma lesions paired with their morphologically normal mucosae. Lymphoid infiltrates were assessed for the expression of the HLA-E-specific, inhibitory, non-rearranging receptor NKG2A.ResultsHigh HLA-E expression did not significantly correlate with the expression of classical HLA-B and HLA-C molecules, but it did correlate with high expression of its preferential ligand donor HLA-A. In addition, it correlated with lymphoid cell infiltrates expressing the inhibitory NKG2A receptor, and was an independent predictor of good prognosis, particularly in a subset of patients whose tumors express HLA-A levels resembling those of their paired normal counterparts (HLA-A). Thus, combination phenotypes (HLA-Elo-int/HLA-AE and HLA-Ehi/HLA-AE) of classical and non-classical class I HLA molecules mark two graded levels of good prognosis.ConclusionsThese results suggest that HLA-E favors activating immune responses to colorectal carcinoma. They also provide evidence in humans that tumor cells entertain extensive negotiation with the immune system until a compromise between recognition and escape is reached. It is implied that this process occurs stepwise, as predicted by the widely accepted 'immunoediting' model.

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BackgroundThe pathogenic role of beta-HPVs in non melanoma skin cancer (NMSC), is not still completely understood, and literature data indicate that they might be at least cofactors in the development of certain cutaneous squamous cell carcinomas. However, only few reports contain data on basal cell carcinoma (BCC). The HPVs interact with many cellular proteins altering their function or the expression levels, like the p16INK4a and Akt. Our study aimed to determine the presence of different beta -HPV types and the expression of p16INK4a and Akt in BCC, the commonest NMSC, in the normal appearing perilesional skin and in forehead swab of 37 immunocompetent patients.MethodsThe expression of p16INK4a and Akt, by immunohistochemistry, and the HPV DNA, by nested PCR, were investigated in each sample.ResultsNo correspondence of HPV types between BCC and swab samples was found, whereas a correspondence between perilesional skin and BCC was ascertained in the 16,7% of the patients. In BCC, 16 different types of beta HPV were found and the most frequent types were HPV107 (15,4%), HPV100 (11,5%) and HPV15 (11,5%) all belonging to the beta HPV species 2. Immunohistochemistry detected significant p16INK4a expression in almost all tumor samples (94,3%) with the highest percentages (> 30%) of positive cells detected in 8 cases. A statistically significant (p = 0,012) increase of beta HPV presence was detected in p16INK4a strongly positive samples, in particular of species 2. pAkt expression was detected in all tumor samples with only 2 cases showing rare positive cells, whereas Akt2 expression was found in 14 out of 35 BCC (40%); in particular in HPV positive samples over-expressing p16INK4a.ConclusionsOur data show that p16INK4a and pAkt are over-expressed in BCC and that the high expression of p16INK4a and of Akt2 isoform is often associated with the presence of beta-HPV species 2 (i.e. HPV 15). The association of these viruses with the up-regulation of p16INK4a and Akt/PI3K pathway suggests that in a subtype of BCC these viruses may exert a role in the carcinogenesis or in other, still undefined, biological property of these tumors. If this particular type of BCC reflects a different biology it will remain undisclosed until further studies on a larger number of samples will be performed.

Little is known regarding the natural history of anal human papillomavirus (HPV) infection. We aimed to evaluate incidence and clearance rates, their risk factors, and duration of anal HPV infection in HIV-uninfected men who have sex with men (MSM). A longitudinal study was conducted. Anal samples were analysed using the Linear Array HPV Genotyping test. Incidence and clearance rates, and corresponding risk factors, were estimated using a two-state Markov model. Overall, 155 MSM (median age 33.4 years) attending the largest sexually transmitted infection (STI) centre in Rome, Italy, were followed for a median of 12.2 months (Q1-Q3: 7.0-18.1). Incidence and clearance rates for any HPV were 85.6 (95% CI: 58.4-125.4) and 35.6 (95% CI: 24.7-51.5) × 1000 person-months, respectively; the median duration of infection was 9.4 months (Q1-Q3: 7.5-12.1). Receptive anal sex emerged as the only risk factor for the acquisition of any HPV (Hazard Ratio, HR = 2.65, 95% CI: 1.16-6.06). The incidence rates for carcinogenic and non-carcinogenic types were 42.3 (95% CI: 29.2-61.4) and 29.2 (95% CI: 19.5-43.7) × 1000 person-months, respectively (p = 0.13); their clearance rates were 62.9 (95% CI: 45.1-87.7) and 65.7 (95% CI: 47.4-91.0) × 1000 person-months, respectively (p = 0.83). HPV16 showed the lowest clearance rate among carcinogenic types (59.7 × 1000 person-months), and a duration of infection of 16.8 months. In conclusion, a higher incidence rate was observed for carcinogenic compared to non-carcinogenic HPV types, although the difference was not significant. HPV16 emerged as the type with the longest duration of infection and the lowest clearance rate among carcinogenic types.

Head and neck squamous cell carcinoma is typically characterized by a high incidence of local recurrences. It has been extensively shown that mucosa from head and neck squamous cell carcinoma patients carries both genetic and gene expression alterations, which are mostly attributable to major etiologic agents of head and neck squamous cell carcinoma. We previously identified a signature of microRNAs (miRNAs) whose high expression in tumors is predictive of recurrence. Here, we investigated whether the deregulation of miRNA expression in the tumor-surrounding mucosa is correlated to disease recurrence. Specifically, comparing the miRNA expression in matched tumoral, peritumoral, and normal tissues collected from head and neck squamous cell carcinoma patients, we identified 35 miRNAs that are deregulated in both tumoral and peritumoral tissues as compared with normal matched samples. Four of these composed a miRNA signature that predicts head and neck squamous cell carcinoma local recurrence independently from prognostic clinical variables. The predictive power of the miRNA signature increased when using the expression levels derived from both the peritumoral and the tumoral tissues. The expression signal of the miRNAs composing the predictive signature correlated with the transcriptional levels of genes mostly associated with proliferation. Our results show that expression of miRNAs in tumor-surrounding mucosa may strongly contribute to the identification of head and neck squamous cell carcinoma patients at high risk of local recurrence.

Dual staining for p16 and Ki-67 demonstrated good reproducibility, confirming its robustness, which is a necessary prerequisite for its adoption as a triage test in cervical cancer screening programs that use human papillomavirus DNA as a primary test. Cancer Cytopathol 2017;125:212-220. © 2016 American Cancer Society.

BackgroundOral Human Papillomavirus (HPV) infection is rare in the general population but common in high-risk individuals. Recent data indicate that oral HPV is associated with the development of head and neck carcinomas. HPV16 infection, in particular, increases the risk of oropharyngeal cancer.MethodsWe evaluated oral HPV prevalence and determinants of infection in cancer-free HIV-infected and uninfected men who have sex with men (MSM) recruited among attendees of an STI/HIV centre. Oral rinse and gargles were collected using a mouthwash and analyzed with the Linear Array HPV Genotyping Test. Socio-demographic and behavioral data were collected through face-to-face interviews.ResultsOverall, 170 MSM participated: 98 HIV-uninfected and 72 HIV-infected (91.7% under cART). Oral HPV was detected in 17.3% and 27.8% of the subjects, respectively (p = 0.13). Non-carcinogenic HPVs were significantly more common among HIV-infected MSM (18.1% vs. 5.1%, p = 0.01). Prevalence of the HPV types included in the quadrivalent HPV vaccine was similar (6.1% vs. 8.3% for the HIV-negative and positive MSM, respectively, p = 0.76). HPV16 was the most frequent type in HIV-negative (5.1%), and HIV-positive individuals, in the latter group together with HPV18, 72 and 84 (4.2% each). Older age at first sex (AOR: 4.02, 95% CI: 1.17–13.86 for those older than 18 years of age at first intercourse, p = 0.027) and a higher lifetime number of receptive oral sex partners (AOR: 9.14, 95% CI: 2.49–33.62 for those with >50 compared to ≤50 partners, p<0.001) were determinants of oral HPV among HIV-infected MSM.ConclusionOral HPV infection among MSM attending an urban STI center is very frequent compared to the general population. Sexual behavior appears to be the major determinant of infection among the HIV-infected individuals.

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