Background: Human 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 expressedin vivoon tumor cells remains to be established.Methods: Taking 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.Results: High 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-E^lo-int/HLA-AE and HLA-E^hi/HLA-AE) of classical and non-classical class I HLA molecules mark two graded levels of good prognosis.Conclusions: These 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.

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favorable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhibition of autophagy sensitized HPV-negative OPSCC cells to the cytotoxic effects of cisplatin. Importantly, semi-quantitative immunohistochemical analysis in primary OPSCCs confirmed that AMBRA1 expression is reduced in HPV-positive compared to HPV-negative tumors. Collectively, these data identify AMBRA1 as a key target of HPV to impair autophagy and propose the targeting of autophagy as a viable therapeutic strategy to improve treatment response of HPV-negative OPSCC. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; CDDP: cisplatin (CDDP); FFPE: formalin-fixed paraffin-embedded (FFPE); HNC: head and neck cancers (HNC); HPV: human papillomavirus (HPV); hrHPV: high risk human papillomavirus (hrHPV); OCSCC: oral cavity squamous carcinomas (OCSSC); OPSCC: oropharyngeal squamous cell carcinoma (OPSCC); OS: overall survival (OS); qPCR: quantitative polymerase chain reaction; RB1: RB transcriptional corepressor 1; ROC: receiver operating characteristic curve (ROC).

Microbiome gained attention as a cofactor in cancers originating from epithelial tissues. High-risk (hr)HPV infection causes oropharyngeal squamous cell carcinoma but only in a fraction of hrHPV+ individuals, suggesting that other factors play a role in cancer development. We investigated oral microbiome in cancer-free subjects harboring hrHPV oral infection (n = 33) and matched HPV− controls (n = 30). DNA purified from oral rinse-and-gargles of HIV-infected (HIV+) and HIV-uninfected (HIV−) individuals were used for 16S rRNA gene V3–V4 region amplification and sequencing. Analysis of differential microbial abundance and differential pathway abundance was performed, separately for HIV+ and HIV− individuals. Significant differences in alpha (Chao-1 and Shannon indices) and beta diversity (unweighted UniFrac distance) were observed between hrHPV+ and HPV-negative subjects, but only for the HIV− individuals. Infection by hrHPVs was associated with significant changes in the abundance of Saccharibacteria in HIV+ and Gracilibacteria in HIV− subjects. At the genus level, the greatest change in HIV+ individuals was observed for Bulleidia, which was significantly enriched in hrHPV+ subjects. In HIV− individuals, those hrHPV+ showed a significant enrichment of Parvimonas and depletion of Alloscardovia. Our data suggest a possible interplay between hrHPV infection and oral microbiome, which may vary with the HIV status.