Oestrogen controls Foxp3 expression in regulatory T cells (T_reg cells) via a mechanism thought to involve oestrogen receptor alpha (ERα), but the molecular basis and functional impact of ERα signalling in T_reg cells remain unclear. We report that ERα ligand oestradiol (E2) is significantly increased in human cervical cancer (CxCa) tissues and tumour-infiltrating T_reg cells (CD4⁺CD25^hiCD127^low), whereas blocking ERα with the antagonist ICI 182,780 abolishes FOXP3 expression and impairs the function of CxCa infiltrating T_reg cells. Using a novel approach of co-immunoprecipitation with antibodies to E2 for capture, we identified binding of E2:ERα complexes to FOXP3 protein in CxCa-derived T_reg cells. Chromatin immunoprecipitation analyses of male blood T_reg cells revealed ERα occupancy at the FOXP3 promoter and conserved non-coding DNA elements 2 and 3. Accordingly, computational analyses of the enriched regions uncovered eight putative oestrogen response elements predicted to form a loop that can activate the FOXP3 promoter. Together, these data suggest that E2-mediated ERα signalling is critical for the sustenance of FOXP3 expression and T_reg cell function in human CxCa via direct interaction of ERα with FOXP3 promoter. Overall, our work gives a molecular insight into ERα signalling and highlights a fundamental role of E2 in controlling human T_reg cell physiology.

Background: For various cancers, differences in response to treatment and subsequent survival period have been reported to be associated with variation in immune contextures.Aim: We sought to identify whether such association exists in respect of gingivobuccal oral cancer.Materials and methods: We performed deep immune profiling of tumor and margin tissues collected from 46 treatment naïve, Human Papillomavirus (HPV) negative, patients. Each patient was followed for 24 months and prognosis (recurrence/death) noted. Key findings were validated by comparing with TCGA‐HNSC cohort data.Results: About 28% of patients showed poor post‐treatment prognosis. These patients exhibited a high probability of recurrence even within 1 year and death within 2 years. There was restricted immune cell infiltration in tumor, but not in margin, among these patients. Reduced expression of eight immune‐related genes (IRGs) (NT5E, THRA, RBP1, TLR4, ITGA6, BMPR1B, ITGAV, SSTR1) in tumor strongly predicted better quality of prognosis, both in our patient cohort and in TCGA‐HNSC cohort. Tumors of patients with better prognosis were associated with (a) lower CD73+ cells with concomitant lower expression level of NT5E/CD73, (b) higher proportions of CD4+ and CD8+ T cells, B cells, NK cells, M1 macrophages, (c) higher %Granzyme+ cells, (d) higher TCR and BCR repertoire diversities. CD73 expression in tumor was associated with low CD8+ and CD4+ T cells, low immune repertoire diversity, and advanced cancer stage.Discussion and conclusion: High infiltration of anti‐tumor immune cells in both tumors and margins results in good prognosis, while in patients with minimal infiltration in tumors in spite of high infiltration in margins results in poor prognosis. Targeted CD73 immune‐checkpoint inhibition may improve clinical outcome.

Using microarray analysis, we found that HOX transcript antisense intergenic RNA (HOTAIR) is up-regulated by Jumonji domain containing-6 (JMJD6), a bifunctional lysyl hydroxylase and arginine demethylase. In breast cancer, both JMJD6 and HOTAIR RNAs increase tumor growth and associate with poor prognosis but no molecular relationship between them is known. We show that overexpression of JMJD6 increased HOTAIR expression and JMJD6 siRNAs suppressed it in ER+ MCF-7, triple negative MDA-MB-231 and non-breast cancer HEK 293 cells. Therefore, JMJD6 regulates HOTAIR independent of ER status. Using various deletion constructs spanning (−1874 to +50) of the HOTAIR promoter, we identified pHP216 (−216 to +50 bp) as the smallest construct that retained maximal JMJD6 responsiveness. In ChIP assays, JMJD6 bound this region suggesting that JMJD6 may be directly recruited to the HOTAIR promoter. Mutant JMJD6H187A that is devoid of enzymatic activity could bind this site but failed to induce transcription. ChIP and electromobility shift assays identified a JMJD6 interaction region from (−123 to −103 bp) within the HOTAIR promoter. In tumor samples but not normal breast tissue, the expression of JMJD6 linearly correlated with HOTAIR suggesting that JMJD6-mediated up-regulation may occur specifically in tumors. Further, concurrent high expression of both genes correlated with poor survival when individual expression of either gene showed no significant association in TCGA datasets. We propose that high JMJD6 expression may achieve higher levels of HOTAIR in breast tumors. Further, since high levels of HOTAIR promote metastasis and death, blocking JMJD6 may be useful in preventing such events.

Head and neck squamous cell carcinoma (HNSCC) is responsible for a large number of deaths each year. Oral cancer is the most frequent subtype of HNSCC. Historically, oral cancer has been associated with an increase in the consumption of tobacco and alcohol products, seen especially in the Asian subcontinent. It has also been associated with infection by the human papilloma virus (HPV), particularly strain HPV16. Treatment usually involves a multidisciplinary approach of surgery combined with chemotherapy and radiation. The advent of immunotherapy has broadened the scope for treatment. A better immune response to the tumour can also elicit the action of other therapeutic approaches. A heightened immune response, on the other hand, can lead to resistant tumour formation through the process of immunoediting. Molecular profiling of the tumour microenvironment (TME) can provide us with better insight into the mechanism and progression of the disease, ultimately opening up new therapeutic options. High-throughput molecular profiling techniques over the past decade have enabled us to appreciate the heterogeneity of the TME. In this review, we will be describing the clinicopathological role of the immune and genomic landscape in oral cancer. This study will update readers on the several immunological and genetic factors that can play an important function as predictive and prognostic biomarkers in various forms of head and neck cancer, with a special emphasis on oral carcinoma.

Oral squamous cell carcinoma (OSCC) includes tumors of the lips, tongue, gingivobuccal complex, and floor of the mouth. Prognosis for OSCC is highly heterogeneous, with overall 5-year survival of ~50%, but median survival of just 8–10 months for patients with locoregional recurrence or metastatic disease. A key feature of OSCC is microenvironmental oxygen depletion due to rapid growth of constituent tumor cells, which triggers hypoxia-associated signaling events and metabolic adaptations that influence subsequent tumor progression. Better understanding of leukocyte responses to tissue hypoxia and onco-metabolite expression under low-oxygen conditions will therefore be essential to develop more effective methods of diagnosing and treating patients with OSCC. This review assesses recent literature on metabolic reprogramming, redox homeostasis, and associated signaling pathways that mediate crosstalk of OSCC with immune cells in the hypoxic tumor microenvironment. The likely functional consequences of this metabolic interface between oxygen-starved OSCC and infiltrating leukocytes are also discussed. The hypoxic microenvironment of OSCC modifies redox signaling and alters the metabolic profile of tumor-infiltrating immune cells. Improved understanding of heterotypic interactions between host leukocytes, tumor cells, and hypoxia-induced onco-metabolites will inform the development of novel theranostic strategies for OSCC.