HPV+ and HPV- head and neck squamous cell carcinoma by analysis of tumor microenviroment

Background: Head and neck squamous cell carcinomas (HNSCCs) are particularly aggressive epithelial tumors, that affect more than half a million patients worldwide each year. They represent a multi-factorial group of tumors caused by: alcohol, tobacco, and human papillomavirus (HPV) infections. Over the last ten years the overall 5-year survival rate of HNSCCs remained ~40–50%, inspite of significant improvement in clinical outcome of many tumor types. There are recent data that claim how some of these cells fulfill a suppressive role in the antitumor immune response. It is interesting that new clinical studies demonstrated that HPV (+) HNSCCs were among tumors with the highest immune infiltrates, while HPV (-) presented a reduced number of immune infiltrating cells. Conclusions: Recent researches prove that tumor microenvironment of HNSCC has an important role in tumor progression, aggressivity, metastasis process, in addition to genetic aberrations and molecular alterations of cancer cells. New researches in stromal composition of the HNSCC may be useful in understanding of mechanisms of different responses to therapy, also can be used as a target for therapeutic purposes. Cancer-associated fibroblasts and immune cells, as well as their products found in neck squamous cell carcinoma significantly influence the biological properties of this tumor. Smoking is one of the risk factors of occurrence of most HPV-associated tumors. Promoting smoking cessation should become an essential contributor to the treatment of cancer in all oncologic pathologies. In cases when patients can’t quit smoking completely within the shortest possible period of time, doctors should focus on harm reduction strategies – tobacco harm reduction.

Characterization of Tumor-immune Microenvironment by High-throughput Image Analysis of CD8 Immunohistochemistry Combined With Modified Masson’s Trichrome

With the advent of checkpoint inhibitors, there is increasing need to study the dynamics of CD8+ T-cells in the tumor microenviroment. In this article, we describe a semi-automated method to quantify and interrogate spatial relationships between T-cells and collagenous stroma in human and mouse tissue samples. The assay combines CD8 immunohistochemistry with modified Masson’s trichrome. Slides are scanned and digital images are analyzed using an adjustable MATLAB algorithm, allowing for high-throughput quantification of cytotoxic T-cells and collagen. This method provides a flexible tool for unbiased quantification of T-cells and their interactions with tumor cells and tumor microenvironment in tissue samples.

The Mevalonate Pathway, a Metabolic Target in Cancer Therapy

A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.

Bioinformatics analysis reveals the ceRNA co-expression network in tumor microenvironment and prognostic biomarkers in Sarcomas

Background Sarcomas (SARCs) are rare, heterogeneous mesenchymal neoplasia. To understand the tumor microenviroment (TME) and identify potential biomarkers for prognosis that associated with TME of SARCs might provide effective clues for immune therapy. Methods We evaluated the immune scores and stromal scores by using the RNA sequencing dataset of SARCs patients from The Cancer Genome Atlas (TCGA) database and the ESTIMATE algorithm. Then the differentially expressed mRNAs (DEGs), miRNAs (DEMs) and lncRNAs (DELs) were filtered after comparing the two high- and low- scores groups. Next, based on these DERNAs, we established a competing endogenous RNA (ceRNA) network and explored the prognostic roles of biomarkers involved in the network with the help of bioinformatics analysis. Results High immune scores were significantly associated with favorable overall survival of SARCs patients. Next, a total of 328 DEGs, 18 DEMs and 67 DELs that commonly regulated in the immune and stromal scores groups were obtained. And for the DEGs, some of the Gene Ontology (GO) terms and pathways were mainly associated with immune processes. A ceRNA network were constructed with 142 nodes and 424 edges, in which hsa-miR-9-5p, hsa-miR-490-3p, hsa-miR-133a-3p, hsa-miR-133b and hsa-miR-129-5p were the top 5 nodes. Additionally, the protein-protein Interaction (PPI) network identified MMP9, TYROBP, CSF1, CXCR4, FBN1, FLNA, PDGFRB, CYBB, FCGR3A and MYH11 as hub nodes with considerable importance that functioned in the network. Finally, the Kaplan-Meier survival analysis demonstrated that 9 mRNAs (APOL1, EFEMP1, LYZ, MEDAG, MYH11, RARRES1, TNFAIP2, TNFSF10 and ZNF385A), 2 miRNAs (hsa-miR-9-5p and hsa-miR-183-5p) and 3 lncRNAs (CTD-2228K2.7, HOTAIRM1 and NCF1C) were closely associated with the overall survival of SARCs patients. Conclusions Taken together, our study confirmed that the prognosis value of immune scores for SARCs patients, also we identified a list of TME-related biomarkers which might contribute to prognostic prediction and help improve the efficacy of immune therapy.

Immune Landscape in Burkitt Lymphoma reveals M2-macrophage polarization and Correlation between PD-L1 expression and Non-Canonical EBV latency program

BACKGROUND: The Tumor Microenviroment (TME) is a complex milieu that is increasingly recognized as a key factor in multiple stages of disease progression and responses to therapy as well as escape from immune surveillance. However, the precise contribution of specific immune effector and immune suppressor components of the TME in Burkitt lymphoma (BL) remains poorly understood.METHODS: In this paper, we applied the computational algorithm CIBERSORT to Gene Expression Profiling (GEP) datasets of 40 BL samples to draw a map of immune and stromal components of TME. Furthermore, by multiple immunohistochemistry (IHC) and multispectral immunofluorescence (IF), we investigated the TME of additional series of 40 BL cases to evaluate the role of the Programmed Death-1 and Programmed Death Ligand-1 (PD-1/PD-L1) immune checkpoint axis. RESULTS: Our results indicate that M2 polarized macrophages are the most prominent TME component in BL. In addition, we investigated the correlation between PD-L1 and latent membrane protein-2A (LMP2A) expression on tumour cells, highlighting a subgroup of BL cases characterized by a non-canonical latency program of EBV with an activated PD-L1 pathway. CONCLUSION: In conclusion, our study analysed the TME in BL and identified a tolerogenic immune signature highlighting new potential therapeutic targets.

Immune Landscape in Burkitt Lymphoma reveals M2-macrophage polarization and Correlation between PD-L1 expression and Non-Canonical EBV latency program

BACKGROUND: The Tumor Microenviroment (TME) is a complex milieu that is increasingly recognized as a key factor in multiple stages of disease progression and responses to therapy as well as escape from immune surveillance. However, the precise contribution of specific immune effector and immune suppressor components of the TME in Burkitt lymphoma (BL) remains poorly understood.METHODS: In this paper, we applied the computational algorithm CIBERSORT to Gene Expression Profiling (GEP) datasets of 40 BL samples to draw a map of immune and stromal components of TME. Furthermore, by multiple immunohistochemistry (IHC) and multispectral immunofluorescence (IF), we investigated the TME of additional series of 40 BL cases to evaluate the role of the Programmed Death-1 and Programmed Death Ligand-1 (PD-1/PD-L1) immune checkpoint axis. RESULTS: Our results indicate that M2 polarized macrophages are the most prominent TME component in BL. In addition, we investigated the correlation between PD-L1 and latent membrane protein-2A (LMP2A) expression on tumour cells, highlighting a subgroup of BL cases characterized by a non-canonical latency program of EBV with an activated PD-L1 pathway. CONCLUSION: In conclusion, our study analysed the TME in BL and identified a tolerogenic immune signature highlighting new potential therapeutic targets.

Immune Landscape in Burkitt Lymphoma Reveals M2-Macrophage Polarization and Correlation between PD-L1 Expression and Non-Canonical EBV Latency Program

The Tumor Microenviroment (TME) is a complex milieu that is increasingly recognized as a key factor in multiple stages of disease progression and responses to therapy as well as escape from immune surveillance. However, the precise contribution of specific immune effector and immune suppressor components of the TME in Burkitt lymphoma (BL) remains poorly understood. In this paper, we applied the computational algorithm CIBERSORT to Gene Expression Profile (GEP) datasets of 40 BL samples to draw a map of immune and stromal components of TME. Furthermore, by VECTRA multispectral immunofluorescence (IF) and multiple immunohistochemistry (IHC), we investigated the TME of an additional series of 40 BL cases and evaluated the possible role of the PD-1/PD-L1 immune checkpoint axis. Our results indicated that M2 polarized macrophages are the most prominent TME component in BL. In addition, we investigated the correlation between PD-L1 and latent membrane protein-2A (LMP2A) expression on tumour cells, highlighting a subgroup of BL cases characterized by a non- canonical latency program of EBV with an activated PD-L1 pathway. In conclusion, our study analysed the TME in BL and identified a tolerogenic immune signature highlighting new potential therapeutic targets.

Carbon Nanotubes as A High-Performance Platform for Target Delivery of Anticancer Quinones

<P>Background: In spite of considerable efforts of researchers the cancer deseases remain to be incurable and a percentage of cancer deseases in the structure of mortality increases every year. At that, high systemic toxicity of antitumor drugs hampers their effective use. Because of this fact, the development of nanosystems for targeted delivery of antitumor drugs is one of the leading problem in nanomedicine and nanopharmacy. </P><P> Objective: To critically examine the modern strategies for carbon nanotubes (CNTs)-based delivery of anticancer quinones and to summarize the mechanisms which can provide high effectiveness and multifunctionality of the CNT-based quinone delivery platform. </P><P> Results: Quinones, including anthracycline antibiotics – doxorubicin and daunorubicin, are among the most prospective group of natural and syntetic compounds which exhibit high antitumor activity against different type of tumors. In this review, we focus on the possibilities of using CNTs for targeted delivery of antitumor compounds with quinoid moiety which is ordinarily characterized by high specific interaction with DNA molecules. Quinones can be non-covalently adsorbed on CNT surface due to their aromatic structure and π-conjugated system of double bonds. The characteristic features of doxorubicine-CNT complex are high loading efficiency, pH-dependent release in acidic tumor microenviroment, enough stability in biological fluid. Different types of CNT functionalization, targeting strategies and designs for multifunctional CNT-based doxorubicine delivery platform are disscussed. </P><P> Conclusion: Nanosystems based on functionalized CNTs are very promising platform for quinone delivery resulting in significant enhancement of cancer treatment efficiency. Functionalization of CNTs with the polymeric shell, especially DNA-based shells, can provide the greatest affinity and mimicry with biological structures.</P>