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Myelodysplastic syndromes (MDS) and their progression to secondary acute myeloid leukemia (sAML) are associated with an altered protein expression including extracellular matrix (ECM) components thereby promoting an inflammatory environment. Since the role of the proteoglycan biglycan (BGN) as an inflammatory mediator has not yet been investigated in both diseases and might play a role in disease progression, its expression and/or function was determined in cell lines and bone marrow biopsies (BMBs) of MDS and sAML patients and subpopulations of MDS stem cells by Western blot and immunohistochemistry. The bone marrow (BM) microenvironment was analyzed by multispectral imaging, patients' survival by Cox regression. ROC curves were assessed for diagnostic value of BGN. All cell lines showed a strong BGN surface expression in contrast to only marginal expression levels in mononuclear cells and CD34+ cells from healthy donors. In the MDS-L cell line, CD34-CD33+ and CD34+CD33+ blast subpopulations exhibited a differential BGN surface detection. Increased BGN mediated inflammasome activity of CD34-CD33+TLR4+ cells was observed, which was inhibited by direct targeting of BGN or NLRP3. BGN was heterogeneously expressed in BMBs of MDS and sAML, but was not detected in control biopsies. BGN expression in BMBs positively correlated with MUM1+ and CD8+, but negatively with CD33+TLR4+ cell infiltration and was accompanied by a decreased progression-free survival of MDS patients. BGN-mediated inflammasome activation appears to be a crucial mechanism in MDS pathogenesis implicating its use as suitable biomarker and potential therapeutic target.

Background:A higher incidence of COVID-19 infection was demonstrated in cancer patients, including lung cancer patients. This study was conducted to get insights into the enhanced frequency of COVID-19 infection in cancer.Methods:Using different bioinformatics tools, the expression and methylation patterns of ACE2 and TMPRSS2 were analyzed in healthy and malignant tissues, focusing on lung adenocarcinoma and data were correlated to clinical parameters and smoking history.Results:ACE2 and TMPRSS2 were heterogeneously expressed across 36 healthy tissues with the highest expression levels in digestive, urinary and reproductive organs, while the overall analysis of 72 paired tissues demonstrated significantly lower expression levels of ACE2 in cancer tissues when compared to normal counterparts. In contrast, ACE2, but not TMPRSS2, was overexpressed in LUAD, which inversely correlated to the promoter methylation. This upregulation of ACE2 was age-dependent in LUAD, but not in normal lung tissues. TMPRSS2 expression in non-neoplastic lung tissues was heterogeneous and dependent on sex and smoking history, while it was downregulated in LUAD of smokers. Cancer progression was associated with a decreased TMPRSS2 but unaltered ACE2. In contrast, ACE2 and TMPRSS2 of lung metastases derived from different cancer subtypes was higher than organ metastases of other sites. TMPRSS2, but not ACE2, was associated with LUAD patients’ survival.Conclusions:Comprehensive molecular analyses revealed a heterogeneous and distinct expression and/or methylation profile of ACE2 and TMPRSS2 in healthy lung vs. LUAD tissues across sex, age and smoking history and might have implications for COVID-19 disease.

Background: The small leucine-rich proteoglycans (SLRPs) biglycan (BGN) and decorin (DCN) linked with sulfated glycosaminoglycan (GAG) chains exhibit oncogenic or tumor suppressive potentials depending on the cellular context and association with GAGs. Objective: We hypothesized that structural alterations and expression levels of BGN, DCN and their associated chondroitin sulfate (CS) polymerizing enzymes, dermatan sulfate (DS) epimerases and various sulfatases might be correlated with the tumor (sub)type and patients’ survival. Methods: We acquired breast cancer (BC) and glioma patients’ datasets from cBioPortal and R2 Genomics. Structural alterations and the expression pattern of CS polymerizing enzymes, DS epimerases and carbohydrate sulfotransferases (CHST) were compared to that of BGN and DCN and correlated to their clinical relevance. Results: In BC, no mutations, but amplifications (0.2 – 2.1 %) and deletions (0.05 – 0.4 %) were found in BGN, DCN and CS/DS enzymes. In contrast, missense and/or truncated mutations (0.1 – 0.5 %), but a reduced amplification rate (0 – 1.5 %) were found in glioma. When compared to BC, the structural abnormalities caused altered mRNA expression levels of BGN, DCN, GAG synthesizing enzymes and CHST. Mutations in SLPRs, CHSY1, CHST4 and CHSY3 were correlated with a poor prognosis in glioma, while lack of mutations and copy number variations in the SLRPs, CHSY3, CHST15 and DSE displayed an increased survival in BC. Conclusion: A distinct association of BGN and DCN with CHST, CS polymerizing enzymes and DS epimerases was found in BC and glioma. Thus, a unique pattern of structural alterations and expression, which has clinical relevance, was found for PGs and GAG synthesizing enzymes and CHST in BC and glioma, which might help to identify high-risk patients and to develop personalized therapeutics.

Background PRELP (proline arginine-rich end leucine-rich repeat protein; also Prolargin), a small leucine-rich proteoglycan, functions as a molecule anchoring basement membranes to connective tissues via the interaction with collagens and heparin. PRELP facilitates the binding of cells to glycosaminoglycans as an important regulator of cell adhesion and thus displays pathophysiological features. Melanoma is an immunogenic tumor, whose relationship with immune cells resident in the microenvironment significantly influences cancer cell proliferation, progression and metastasis. Evasion from immune surveillance is a hallmark of melanoma progression. While our laboratory reported that the proteoglycan biglycan (BGN) was enhancing MHC class I in tumor cells,1 the role of PRELP in tumor immunology has not been studied. Methods The murine metastatic melanoma cell line B16F10, characterized by a reduced expression of MHC class I surface antigens was chosen for this study. B16F10 cells were transiently transfected with PRELP as well as co-transfected with BGN. Expression of antigen processing machinery (APM) components and PRELP was determined by qPCR and MHC class I surface expression by flow cytometry. Promoter activity of APM components was analysed by luciferase reporter assays. XTT assays were used to determine cell proliferation. The association of PRELP and MHC class I was studied by bioinformatics in a mixed melanoma dataset of 83 samples.2 Results Over-expression of PRELP in B16F10 cells enhanced the expression of MHC class I surface antigens, which was due to a PRELP-mediated transcriptional upregulation of components of the MHC class I APM components TAP1, TAP2 and TAPBP as determined by qPCR and promoter assay in PRELP transfectants versus mock controls. Furthermore, MHC class I surface expression was even more pronounced upon BGN co-transfection with PRELP. PRELP overexpression was able to inhibit the proliferation of the B16F10 cells. Bioinformatics analyses demonstrated a positive correlation of PRELP with HLA-A , -B and -C alleles in human melanoma. Conclusions Our findings demonstrated that overexpression of PRELP correlates with higher MHC class I expression and inhibits cell proliferation. For the first time, co-transfections of the two proteoglycans PRELP and BGN had a synergistic effect on upregulating MHC class I expression. Therefore, PRELP can serve as a novel therapeutic strategy that deserves further investigation. Acknowledgements The project is supported by Wilhelm-Sander-Stiftung (No: 2019.076.1) and by a Roux grant (FKZ: PK37) of the Medical Faculty of the Martin-Luther-University Halle-Wittenberg. References Subbarayan K, Leisz S, Wickenhauser C, Bethmann D, Massa C, Steven A, Seliger B. Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells. Oncoimmunology 2018;7:e1373233. Xu L, Shen SS, Hoshida Y, Subramanian A, Ross K, Brunet JP, Wagner SN, Ramaswamy S, Mesirov JP, Hynes RO. Gene expression changes in an animal melanoma model correlate with aggressiveness of human melanoma metastases. Molecular Cancer Research 2008;6:760-769.

There exists increasing evidence that people with preceding medical conditions, such as diabetes and cancer, have a higher risk of infection with SARS-CoV-2 and are more vulnerable to severe disease. To get insights into the possible role of the immune system upon COVID-19 infection, 2811 genes of the gene ontology term “immune system process GO: 0002376” were selected for coexpression analysis of the human targets of SARS-CoV-2 (HT-SARS-CoV-2) ACE2, TMPRSS2, and FURIN in tissue samples from patients with cancer and diabetes mellitus. The network between HT-SARS-CoV-2 and immune system process genes was analyzed based on functional protein associations using STRING. In addition, STITCH was employed to determine druggable targets. DPP4 was the only immune system process gene, which was coexpressed with the three HT-SARS-CoV-2 genes, while eight other immune genes were at least coexpressed with two HT-SARS-CoV-2 genes. STRING analysis between immune and HT-SARS-CoV-2 genes plotted 19 associations of which there were eight common networking genes in mixed healthy (323) and pan-cancer (11003) tissues in addition to normal (87), cancer (90), and diabetic (128) pancreatic tissues. Using this approach, three commonly applicable druggable connections between HT-SARS-CoV-2 and immune system process genes were identified. These include positive associations of ACE2—DPP4 and TMPRSS2—SRC as well as a negative association of FURIN with ADAM17. Furthermore, 16 drugs were extracted from STITCH (score

Background There exists increasing evidence that people with preceding medical conditions, such as asthma, diabetes, cancers and heart disease, have a higher risk of infection with SARS-CoV-2 and are more vulnerable to severe disease.Methods To get insights into the role of the immune system upon COVID-19 infection, 2811 genes of the gene ontology term “immune system process GO: 0002376” were selected for analyses. The immune system genes potentially co-expressed with the human targets of SARS-CoV-2 (HT-SARS-CoV-2) ACE2, TMPRSS2 and FURIN were determined in tissue samples from patients with cancer and diabetes mellitus. The network between HT-SARS-CoV-2 and immune system process genes was analyzed based on functional protein associations using STRING. In addition, STITCH was employed to determine druggable targets.Results DPP4 was the only immune system process gene, which was coexpressed with the three HT-SARS-CoV-2 genes, while eight other immune genes were at least co-expressed with two HT-SARS-CoV-2 genes. STRING analysis between immune and HT-SARS-CoV-2 genes plotted 19 associations of 8 commonly networking genes in mixed healthy (323) and cancer (11003) tissues in addition to normal (87), cancer (90) and diabetic (128) pancreatic tissues. Using this approach, three druggable connections between HT-SARS-CoV-2 and immune system process genes were identified. They include positive associations of ACE2 - DPP4 and TMPRSS2 – SRC as well as a negative association of FURIN with ADAM17. Furthermore, the 16 drugs were extracted from STITCH (score Conclusions This bioinformatics pipeline identified for the first time an immunological network associated with COVID-19 infection thereby postulating novel therapeutic opportunities.

The recent COVID-19 outbreak in China led to a worldwide pandemic associated with a severe acute respiratory illness. A higher incidence of COVID-19 infection was demonstrated in cancer patients, including patients with lung cancer. This study was conducted to get insights into the reasons for this enhanced frequency of COVID-19 infection. Methods: Using different bioinformatic tools, the expression and methylation pattern of ACE2 and TMPRSS2 gene were analyzed in healthy and malignant tissues with a focus on lung adenocarcinoma (LUAD) and correlated to clinical parameters and smoking history. Results: ACE2 and TMPRSS2 were heterogeneously expressed across 36 healthy tissues with the highest expression in digestive, urinary and reproductive organs, while their expression was significantly lower in 36 cancer tissues. In LUAD, ACE2, but not TMPRSS2 was overexpressed, which inversely correlated to the promoter methylation. An age-dependent upregulation of ACE2 expression was found in LUAD compared to normal lung tissues. In a healthy lung, TMPRSS2 expression was dependent on sex and smoking history and downregulated in LUAD of smokers. Cancer progression was associated with decreased TMPRSS2, but unaltered ACE2 expression, while ACE2 expression in lung metastases of different cancers was higher than in metastasis of other sites. TMPRSS2, but not ACE2 expression, was associated with LUAD patients’ survival. Conclusions: Comprehensive molecular analyses revealed a heterogeneous, distinct expression and methylation profile of ACE2 and TMPRSS2 in healthy lung vs LUAD tissues across sex, age and smoking history, which is associated with clinical parameters and might have implications for COVID-19 disease.

Immunotherapy aims to activate the immune system to fight cancer in a very specific and targeted manner. Despite the success of different immunotherapeutic strategies, in particular antibodies directed against checkpoints as well as adoptive T-cell therapy, the response of patients is limited in different types of cancers. This attributes to escape of the tumor from immune surveillance and development of acquired resistances during therapy. In this review, the different evasion and resistance mechanisms that limit the efficacy of immunotherapies targeting tumor-associated antigens presented by major histocompatibility complex molecules on the surface of the malignant cells are summarized. Overcoming these escape mechanisms is a great challenge, but might lead to a better clinical outcome of patients and is therefore currently a major focus of research.

The extracellular matrix protein biglycan (BGN) has oncogenic or tumor suppressive potential depending on the cellular origin. HER-2/neu overexpression in murine fibroblasts and human model systems is inversely correlated with BGN expression. Upon its restoration BGNhigh HER-2/neu+ fibroblasts were less tumorigenic in immune competent mice when compared to BGNlow/neg HER-2/neu+ cells, which was associated with enhanced immune cell responses and higher frequencies of immune effector cells in tumors and peripheral blood. The increased immunogenicity of BGNhigh HER-2/neu+ fibroblasts appears to be due to upregulated MHC class I surface antigens and reduced expression levels of transforming growth factor (TGF)-β isoforms and the TGF-β receptor 1 suggesting a link between BGN, TGF-β pathway and HER-2/neu-mediated downregulation of MHC class I antigens. Treatment of BGNlow/neg HER-2/neu+ cells with recombinant BGN or an inhibitor of TGF-β enhanced MHC class I surface antigens in BGNlow/neg HER-2/neu-overexpressing murine fibroblasts, which was mediated by a transcriptional upregulation of major MHC class I antigen processing components. Furthermore, BGN expression in HER-2/neu+ cells was accompanied by an increased expression of the proteoglycan decorin (DCN). Since recombinant DCN also elevated MHC class I surface expression in BGNlow/neg HER-2/neu+ cells, both proteoglycans might act synergistically. This was in accordance with in silico analyses of mRNA data obtained from The Cancer Genome Atlas (TCGA) dataset available for breast cancer (BC) patients. Thus, our data provide for the first time evidence that proteoglycan signatures are modulated by HER-2/neu and linked to MHC class I-mediated immune escape associated with an altered TGF-β pathway.