HAGE, a cancer/testis antigen expressed at the protein level in a variety of cancers

The search for novel tumour antigens that are either uniquely expressed or over-expressed in a wide variety of tumours is still ongoing. Because of their expression in a broad spectrum of cancers and limited expression in normal tissues, cancer/testis antigens are considered to be potentially reliable targets for immunotherapy of cancer in general. The helicase antigen HAGE has been identified as a cancer/testis antigen. However, little is known about its expression in normal and cancer tissues. Using a newly developed antibody against HAGE, specific staining of its expression by immunohistochemistry was validated and optimised on murine tumours transfected to express the HAGE protein. The antibody was subsequently used to determine HAGE expression in normal human and cancer tissue microarrays. HAGE protein expression was confirmed in 75% (12/16) of carcinomas as compared to normal tissues, which either did not express HAGE at all or expressed HAGE at very low levels with the exception of testis. Interestingly, discrepancies were also found between mRNA analysis by real time quantitative PCR (RT-qPCR) and protein analysis by immunohistochemistry, emphasising the need to validate the expression of cancer/testis antigens at the protein level prior to the development of new vaccine strategies. HAGE is therefore proposed to be a valid candidate for designing a broad spectrum vaccine against cancer

Head and neck: Salivary gland tumors: an overview

Review on Head and neck: Salivary gland tumors: an overview, with data on clinics, and the genes involved

Head and Neck: Squamous cell carcinoma: an overview

Review on Head and Neck: Squamous cell carcinoma: an overview, with data on clinics, and the genes involved

Pre-therapeutic histological and cytological assessment in head and neck squamous cell carcinomas. French Society of Otorhinolaryngology Guidelines – 2012

SummaryObjectivesThe authors present the French Society of Otorhinolaryngology (SFORL) guidelines for histopathologic assessment of head and neck cancer.Materiel and methodsA multidisciplinary workgroup set up by the SFORL performed an exhaustive review of the literature according to levels of evidence, following the 2000 guidelines of the French national health approvals and assessment agency (ANAES).ResultsComparison between histologic and clinical data is essential. In case of discrepancy between clinical, radiological and histological findings, reinterpretation or new biopsy may be required (professional consensus). Mere suspicion of carcinoma on fine-needle aspiration lymph-node biopsy only exceptionally warrants aggressive treatment (professional consensus). Exploration for HPV is not recommended as routine practice, being without therapeutic impact (professional consensus). Anti-p16 immunohistochemistry is optional, for epidemiological purposes (professional consensus). Tumor-bank tissue storage must conform strictly to prevailing legislation and good practice rules for sampling and preservation (professional consensus).ConclusionPathology assessment is mandatory in suspected H&N squamous cell carcinoma. The present guidelines are intended to optimize management

Intraparotid Kimura disease

SummaryIntroductionIntraparotid locations are extremely rare in Kimura disease, especially in Europe.Case reportA 31-year-old man presented with intraparotid Kimura disease, managed by parotidectomy.Discussion/conclusionThe case was analyzed in the light of a review of the literature, focusing on the diagnostic and anatomopathologic problems encountered, and the physiopathology and treatment of this pathology. Any parotid mass found in a patient of Far-Eastern origin showing hypereosinophilia should suggest a diagnosis of intraparotid Kimura disease

Modeling tumor cell migration: from microscopic to macroscopic

It has been shown experimentally that contact interactions may influence the migration of cancer cells. Previous works have modelized this thanks to stochastic, discrete models (cellular automata) at the cell level. However, for the study of the growth of real-size tumors with several millions of cells, it is best to use a macroscopic model having the form of a partial differential equation (PDE) for the density of cells. The difficulty is to predict the effect, at the macroscopic scale, of contact interactions that take place at the microscopic scale. To address this we use a multiscale approach: starting from a very simple, yet experimentally validated, microscopic model of migration with contact interactions, we derive a macroscopic model. We show that a diffusion equation arises, as is often postulated in the field of glioma modeling, but it is nonlinear because of the interactions. We give the explicit dependence of diffusivity on the cell density and on a parameter governing cell-cell interactions. We discuss in details the conditions of validity of the approximations used in the derivation and we compare analytic results from our PDE to numerical simulations and to some in vitro experiments. We notice that the family of microscopic models we started from includes as special cases some kinetically constrained models that were introduced for the study of the physics of glasses, supercooled liquids and jamming systems.Comment: Final published version; 14 pages, 7 figure

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells

Immune cells are important components of the tumor microenvironment and influence tumor growth and evolution at all stages of carcinogenesis. Notably, it is now well established that the immune infiltrate in human tumors can correlate with prognosis and response to therapy. The analysis of the immune infiltrate in the tumor microenvironment has become a major challenge for the classification of patients and the response to treatment. The co-expression of inhibitory receptors such as Program Cell Death Protein 1 (PD1; also known as CD279), Cytotoxic T Lymphocyte Associated Protein 4 (CTLA-4), T-Cell Immunoglobulin and Mucin Containing Protein-3 (Tim-3; also known as CD366), and Lymphocyte Activation Gene 3 (Lag-3; also known as CD223), is a hallmark of T cell exhaustion. We developed a multiparametric in situ immunofluorescence staining to identify and quantify at the cellular level the co-expression of these inhibitory receptors. On a retrospective series of frozen tissue of renal cell carcinomas (RCC), using a fluorescence multispectral imaging technology coupled with an image analysis software, it was found that co-expression of PD-1 and Tim-3 on tumor infiltrating CD8 T cells is correlated with a poor prognosis in RCC. To our knowledge, this represents the first study demonstrating that this automated multiplex in situ technology may have some clinical relevance

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P<0.05) and macrophage (P<0.05) infiltration and microvessel density (P<0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P<0.01), negative hormonal receptor (P<0.10), lower albumin concentrations (P<0.01), increased tumour proliferation (P<0.05), increased tumour microvessel density (P<0.05), the extent of locoregional control (P<0.0001) and limited systemic treatment (Pless than or equal to0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P<0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer

IRX-2, a novel biologic, favors the expansion of T effector over T regulatory cells in a human tumor microenvironment model

IRX-2, a natural cytokine biological with multiple components, has been used in preclinical and clinical studies to promote antitumor activity of T lymphocytes. To define cellular mechanisms responsible for antitumor effects of IRX-2, its ability to induce effector T cells (Teff) was examined in a model simulating the tumor microenvironment. An in vitro model containing conventional CD4+CD25− cells co-cultured with autologous immature dendritic cells, irradiated tumor cells, and cytokines was used to study differentiation and expansion of regulatory T cells (Treg) and Teff in the presence and absence of IRX-2. Phenotype, suppressor function, signaling, and cytokine production were serially measured using flow cytometry, Western blots, CFSE-based suppressor assays, and Luminex-based analyses. The presence of IRX-2 in the co-cultures promoted the induction and expansion of IFN-γ+Tbet+ Teff and significantly (p < 0.01) decreased the induction of inducible IL-10+TGF-β+ Treg. The responsible mechanism involved IFN-γ-driven T cell polarization towards Teff and suppression of Treg differentiation. In an in vitro model simulating the human tumor microenvironment, IRX-2 promoted Teff expansion and antitumor activity without inducing Treg. Thus, IRX-2 could be considered as a promising component of future antitumor therapies

The prognostic impact of anti-cancer immune response: a novel classification of cancer patients

Until now, the anatomic extent of tumor (TNM classification) has been, by far, the most important factor to predict the prognosis of colorectal cancer patients. However, in recent years, data collected from large cohorts of human cancers demonstrated that the immune contexture of the primary tumors is an essential prognostic factor for patients' disease-free and overall survival. Global analysis of tumor microenvironment showed that the nature, the functional orientation, the density, and the location of adaptive immune cells within distinct tumor regions influence the risk of relapse events. An immune classification of the patients was proposed based on the density and the immune cell location within the tumor. The immune classification has a prognostic value that is superior to the TNM classification, and tumor invasion is statistically dependent on the host immune reaction. Tumor and immunological markers predicted by systems biology methods are involved in the shaping of an efficient immune reaction and can serve as targets for novel therapeutic approaches. Thus, the strength of the immune reaction could advance our understanding of cancer evolution and have important consequences in clinical practice