Biography:

Manal Saber has completed her PhD from Nottingham University. She is an associate professor of Clinical Pathology, Minia University, Egypt. She has published papers in peer reviewed journals and has been serving as an editorial board member of others. She has interests in Cancer Studies, Immunotherapy and tumor Immunology

Abstract:

Statement of the Problem: Colorectal cancer (CRC) is being currently considered one of the most common, and deadly, malignancies in the world. Many CRC patients are likely to be immunosuppressive. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional cytokine with pro-inflammatory properties. It was demonstrated that EMAP-II induces lymphocytes apoptosis in CRC. The purpose of this study is to investigate the role of EMAP II in immune suppression in CRC.

Methodology & Theoretical Orientation: The immunosuppressive effect of EMAP II was verified by in vivo  and in vitro experiments. The immunosuppressive mechanisms were analysed using flow cytometry, ELISA, immunohistochemistry, and T-lymphocytes assays.

Findings: EMAP II expression in CRC was associated with suppression of T cell activity and decreased infiltrating T cells. EMAP II blockade in mice bearing colorectal cancer reduced tumour burden and increased T cell responses. In this study, we found that colorectal cancer-infiltrating tregs expressed increased levels of EMAP II. Furthermore, EMAP-II levels correlated positively with serum IL-2 and TGF-β (p<0.001).

Conclusion & Significance: This study has demonstrated the role of EMAP II in immune suppression and the potential for immunotherapy via blocking EMAP II in CRC.

Biography:

Leiming Xia is an professor in University of Michigan Comprehensive Cancer Center, USA. he has published many artciles in reputed journals.

Abstract:

Mucin1 (MUC1), as an oncogene, overexpressed in many human carcinomas and plays a key role in the progression and tumorigenesis. MUC1 specific chimeric antigen receptors (CARs) modified T/NK cells has been shown to be an effective approach for inducing MUC1⁺ tumor cells death. However, treatment failure with CAR-T/NK therapy was usually caused by the high expression of negative immune-regulatory molecules in tumor microenvironment. PD-L1 has been identified as negative checkpoint molecules that promote immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes or infused T/NK cells while activating the negative immune-regulatory cells in tumor microenvironment. To conquer these barriers and transform the PD-1/PDL-1 suppression effect into a positive regulation, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express two kinds of chimeric antigen receptors (CARs) comprising an anti-MUC1 or anti-PDL1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD1 peptide. Anti-MUC1-CAR expression by gene-modified NK92 cells specifically and efficiently lysed MUC1 positive tumor cells in vitro and in vivo. In this study, 10 patients with different kinds of tumor (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) were enrolled with PDL-1 and MUC-1 positive through pathological examination, then CAR-NK cells were infused several times into the patients (1×10⁹ cells total). Of 10 patients, 2 patients were withdrawn, 7 patients (70%) showed stable disease and 1 patient (10%) showed progressive disease. We also monitored the cytokines level and hematological changes to evaluate the safety. Most patients didn`t shown cytokine storm or bone marrow suppression obviously. From these patients we found that CAR-NK therapy has a broad prospect of application as a novel immunotherapy related to its certain clinical effects, mild side effects and easy preparing. CAR-NK would play more obviously anti-tumor efficacy through Bi-target treatment.

Biography:

Lu Wen is an professor in University of Michigan Comprehensive Cancer Center, USA. he has published many artciles in reputed journals.

Abstract:

Over the years, the role of B cells in the host immune response to malignancy has been overshadowed by our focus on T cells. The role played by B cells in cancer immunology is complex and controversial.  The observation made by our lab that activated B cells alone can mediate tumor regression in the adoptive immunotherapy of solid tumors is innovative. One novel mechanism by which activated B cells mediate tumor regression is via direct tumor cell cytotoxicity in the absence of antibodies.  We reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10.  In this study, we defined additional mechanisms involved in B cell antitumor immunity.  Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL-2R. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemotraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12-producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional experiments showed that effector B cells could directly kill tumor cells via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor, and clearly indicated that transferred effector B cells can act independently of T cells in causing tumor destruction in adoptive immunotherapy

Biography:

As a PhD candidate, Ms Guohui Qin is majoring in tumor immunology, specially in tumor microenvironment. She has been studying on the role of immunosuppressive cells as myeloid-derived suppressive cells (MDSCs) and tumor initiating cells in the regulation of the proliferation and function of effective T cells in tumor microenvironment. And she has been committed to improve the efficiency of immunotherapy by blocking immunosuppressive factors. Moreover, her reports about “Blocking MDSCs accumulation in tumor site improves clinical prognosis” has been employed in Cold Spring Harbor Asia Conferences.

Abstract:

Backgrounds: Esophageal cancer has become the sixth common reason of cancer death and causes approximately 400,000 deaths worldwide annually. Esophageal cancer can be divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA) according to the histopathology. ESCC mainly distributes in Asia, correlated with smoking and drinking, while the incidence of EA which is related to gastric reflux, Barrett’s esophagus and obesity increased year by year in Western countries. Previous studies have demonstrated TP53 with a high mutation rate in both pathologies, whereas TP63/SOX2, which is associated with cell differentiation, has a high mutation rate in ESCC. However, there are few studies on the expression patterns of tumor-associated immune molecules in esophageal carcinoma. Here, we investigated the correlation between different molecules and the prognosis of different pathological esophageal cancer with the analysis of ESCC, EA and normal tissue from TCGA database. Materials and Methods: In this study, 94 different ESCC and 89 cases of EA were screened for the differentially expressed genes in tumor tissues. We investigate the distribution of increased genes in KEGG pathways. With Venn diagram Analysis we clarify the similarities and differences of gene distribution in the development of ESCC and EA. And the correlation between the screened genes and their prognosis significance was analyzed with Kaplan-Meier methods. Findings: Compared with normal tissues, the expression of 3109 genes in ESCC was increased, while 2571 genes elevated in EA. In further enrichment analysis of the elevated genes, we found that the cytokine-cytokine receptor interaction pathway may play a crucial role in the tumorigenesis and development of esophageal cancer. The Venn diagram Analysis showed that 57 genes were identical in ESCC and EA, but 18 genes were found specially increased in ESCC and other 37 related genes were only significantly elevated in EA. With survival analysis, we got that TNFRSF10B was positively and CXCL14 was negatively correlated with ESCC prognosis. And CXCL8 and IL17RB in EA were negatively correlated with survival. Our further experiments will analyze the role of TNFRSF10B, CXCL14, CXCL8 and IL17RB in ESCC and EA respectively.

Conclusion: Different molecular mechanisms play significant role in occurrence and development in ESCC and EA, which determines the different prognosis and target treatment in esophageal carcinoma.

Biography:

Abstract:

Cancers are among the leading causes of death worldwide, entailing also what is now called financial toxicity. Conventional treatment modalities (surgery, chemo-­â€ and radiotherapy) have considerable limitations, which often result in incomplete destruction of the tumors. Therefore, prevention and control of cancer diseases is an important task for today’s medicine, due to the possible implications of such diseases on public health and to their economic consequences. And to their economic consequences. Therefore, the development of new therapeutic strategies to fight cancer is a priority for research. In this regard, the use of bacteria as alternative cancer therapeutics, in particular their potential to selectively target cancer cells has been studied for more than a century.

We, therefore investigated the tumor targeting efficacy and the mechanism of action of a specific attenuated mutant strain of Salmonella Typhimurium (STMznuABC) devoid of the whole operon coding for the high-­â€affinity zinc transporter ZnuABC, which is required for bacterial growth in environments poor in zinc and for conferring full virulence to different Gram-­â€negative pathogens.

The results indicated that STMznuABC is able to penetrate and replicate into tumor cells in in- vitro and in vivo models. The subcutaneous administration of STMznuABC in mammary adenocarcinoma mouse model leads to both reduction of tumor growth and increase in life expectancy of STMznuABC treated mice. Moreover, investigating the potential mechanism behind the favorable clinical outcomes, we provide evidence that STMznuABC stimulates a potent inflammatory response and a specific immune pattern, recruiting a large number of innate and adaptive immune cells capable to contrast the immunosuppressive environment generated by tumors. Exploring the tumor microenvironment of STMznuABC-­â€treated mice, we found that STMΔznuABC is able to increase the number of neutrophil cells, interferon gamma CD8+ cells and a Th1 immune profile phenotype. On the whole, our results support the potential STM as a promising anti-­â€cancer therapy.

Biography:

Dr. Zarina Arif, has completed her Ph.D. in the year 1993 from Aligarh Muslim University, India. She has work as Research Assistant (23-9-1993 to 22-7-2008) at the College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia. It was research cum teaching job. She has worked as Research Associate for six month at Department of Biochemistry, Faculty of Medicine, AMU, Aligarh. She also worked as Postdoctoral Fellow of the University Grants Commission, New Delhi since 11 Feburary 2012 to 30 July 2015. She is presently working as Assistant Professor at the Department of Biochemistry, J.N.  Medical College, Aligarh, India. She has attended several national and international conferences and has published 25 papers in international journals

Abstract:

Statement of purpose: Extensive research till date suggests that oxidative stress, chronic inflammation, and cancer are closely linked. Inflammation results in the production of numerous reactive oxygen, nitrogen and chlorine species, in addition to the products of lipid and sugar oxidation, some of these products are capable of chemically modifying amino acids in proteins. This in turn results in changes to the structure and function of proteins. Increasing evidence demonstrates that such post-translational modifications result in the generation of neo-epitopes capable of eliciting both innate and adaptive immune responses. Therefore, this study has analyzed the changes in human serum albumin upon modification with peroxynitrite, an endogenously produced powerful oxidizing and nitrating agent, and is implication in the etiopathogenesis of cancer. 

Methodology & Theoretical Orientation: Various physico-chemical studies were carried out to establish the modification of albumin. Peroxynitrite-modified-albumin exhibited hyperchromicity at 278 nm, changed microenvironment of tyrosine, tryptophan along with the generation of 3-nitrotyrosine, nitrotryptophan and protein carbonyls. Moreover, we have observed immune cells may generate autoantibodies. Thus, peroxynitrite-modified-albumin was used as antigen for detecting autoantibodies in lung cancer patients by ELISA. IgG isolated from the sera of patients with lung cancer showed better recognition for neo-epitopes on the modified albumin, reflecting theresence of circulating autoantibodies in lung cancer patients. 

Conclusion and Significance: Gross structural changes in albumin may favour autoantibodies induction in vivo under similar conditions. Peroxynitrite- modified –albumin may also be considered as potential antigenic candidates for eliciting autoimmune response in lung cancer patients.

Biography:

Abstract:

Biography:

Mai Moaaz is an assistant professor of Immunology. She has a passion in the field of tumor immunology and an expertise in tumor tissue culture system and experimenting new modalities for cancer immunotherapy. Her tissue culture system provides the ex vivo tissue architecture that is necessary to maintain or reconstitute an environment closely resembling that of the tumor tissue to reflect the complex tissue architecture of an individual tumor. The majority of preclinical cancer research is based on established cell lines that frequently have undergone multiple changes influencing their biological behavior and therefore no longer reflect that of the primary tumor of origin. She has built this model after years of experience in research, evaluation, teaching and administration both in hospital and education institutions. She is conducting current studies on tumors as an approach to cancer immunotherapy.

Abstract:

Statement of the Problem: Because of heterogeneity of gastric cancer (GC), searching for more accurate predictors of GC prognosis has become a growing interest. Infiltration of immune cells in tumors is associated with prognosis; among them are the immunosuppressive myeloid derived cells (MDSCs). Their accumulation constitutes an important mechanism of tumor immune evasion. Hence, their characterization is essential for diagnosis and therapeutics of cancer. Increased expression of microRNA-494 was noticed in MDSCs from tumor-bearing mice suggesting another new therapeutic objective for cancer treatment. It was also discovered that tumor-derived transforming growth factor beta (TGF-β) was responsible for the up-regulation of microRNA-494 in MDSCs.  The purpose of this study is to address the suppressive effect of MDSCs on T cells in GC and its possible association with Micro-RNA-494 and TGF-β expression in tumor tissue. Methodology & Theoretical Orientation: A case control study on 40 GC patients and corresponding controls where done. Tissue samples and peripheral blood were used for isolation of CD33+11b+HLADR- MDSCs cells using flowcytometry. MDSCs were co-cultured with isolated T cells to assess proliferation and cytokine production. Real-time PCR and Enzyme linked immunosorbent assay were used to evaluate tumor expression of miRNA-494 and TGF-β respectively. Findings: MDSCs percentages were significantly elevated in GC patients than controls and significantly increased in tumor specimens than paraneoplastic tissue. This increased expression is accompanied with elevation of TGF-β production in tumor than surroundings. MiRNA-494 was also extensively expressed in tumor samples. Addition of MDSCs from cancer patients markedly suppressed the proliferation of autologous T cells and cytokine production; however, no inhibitory effect was observed for MDSCs from healthy donors. Conclusion & Significance: The result indicates that tumor-derived MDSCs but not MDSCs from healthy donors have the immunosuppressive effect on T cells. Infiltration of MDSCs in tumors is associated with the prognosis of GC.

Biography:

Mai Moaaz is an assistant professor of Immunology. She has a passion in the field of tumor immunology and an expertise in tumor tissue culture system and experimenting new modalities for cancer immunotherapy. Her tissue culture system provides the ex vivo tissue architecture that is necessary to maintain or reconstitute an environment closely resembling that of the tumor tissue to reflect the complex tissue architecture of an individual tumor. The majority of preclinical cancer research is based on established cell lines that frequently have undergone multiple changes influencing their biological behavior and therefore no longer reflect that of the primary tumor of origin. She has built this model after years of experience in research, evaluation, teaching and administration both in hospital and education institutions. She is conducting current studies on tumors as an approach to cancer immunotherapy.

Abstract:

Statement of the Problem: Breast cancer is the most common cancer in females being the leading cause of cancer mortality in women. The continuous interactions of cancerous cells with their surrounding microenvironment infiltrating immune cells shape their immunogenicity as well as the ability to tumor progression and metastasis. Interleukin 17A (IL-17A) has a promoting role in carcinogenesis, tumor metastasis and resistance to chemotherapy. It enhances tumor cell survival and invasiveness and inhibits the antitumor immune response. Pro-tumor effects of IL-17A may occur via an increase in suppressive functions of myeloid-derived suppressor cells (MDSCs). The expression of IL-17A and programmed death ligand 1 (PDL1) is increased in breast cancer. The PDL1–PD1 (programmed death protein 1) signaling pathway promotes escape from immune surveillance in tumor cells. The purpose of this study is to address the potential suppressive effects of monoclonal anti-IL-17 antibodies on IL-17 tumorigenic activities in intact tumor microenvironment of BC as a novel immunotherapeutic reagent. Methodology & Theoretical Orientation: Fresh tumor tissue samples and peripheral blood were taken from 50 BC patients. IL-17A and PDL1 expression were primarily assessed. Cultures of tumor tissues either supplemented or not with anti-IL-17 monoclonal antibodies were subjected to evaluation of PDL1, MDSCs and T cell activities. Findings: Our results revealed that IL-17A stimulated PDL1 expression in tumor BC cultures and were correlated to clinicopathological features. Culturing with anti-IL-17 monoclonal antibodies suppressed PDL1 expression, and promoted T cell proliferation and functions. Tumors cultured with anti-IL-17 showed a significant decrease in the expression of MDSCs cells in the tumor microenvironment. Conclusion & Significance: The results indicate that recombinant anti-IL-17 monoclonal antibodies could represent a novel effective element of immunotherapeutic treatment strategy for BC. The selectivity and anti- potential of anti-IL-17 is highly hopeful in IL-17- abundant BC tumor microenvironment. 

Biography:

Naoki Otsu is interested in stem cell biology and tumorigenesis from stem cells. Based on Cancer stem cell theory, we are searching for cells with high tumorigenicity and membrane proteins intensely expressed in the cells. Currently, we focus on glioblastoma, a malignant brain tumor, and analyze membrane proteins that are molecular targets of antibody drugs. Using induced cancer stem cells derived from neural stem cells as model cells, strongly expressed membrane proteins were searched for multiple candidate proteins. This presentation introduces the molecules whose function and molecular mechanism are clarified among the obtained candidate.

Abstract:

Research focused on the property and targets of cancer stem cells, which have tumorigenicity and treatment-resistant, may contribute to the discovery of new therapeutic and diagnostic strategies. We have previously established mouse glioma-initiating cell (mGIC) lines from normal neural lineage cells, analyzed their gene expression profile, and reported functions of GIC-specific genes. We further focused on GIC-specific membrane proteins and found uncharacterized cell-membrane protein Eva1. Here we show the characterization of Eva1 in GIC: Eva1 is highly expressed in mouse GIC line, NSCL61, and human glioblastoma (GBM, WHO grade IV)-derived floating spheres, whereas it is not expressed in normal adult mouse and human brain. Eva1 expression is correlated with the malignancy of glioma. Indeed, we found that Eva1+ cells disseminate in human GBM tissue. Moreover, knockdown of Eva1 inhibited cell proliferation and tumorigenicity in mGIC and hGIC. Forced-expression of Eva1 enhanced malignancy of Low-grade human glioma (Diffuse Astrocytoma: DA, WHO grade II). The combination of polyclonal anti-Eva1 antibody and cytotoxic factor Saporin kills GIC, therefore it promised as a new target of antibody preparation. Using gene expression profiles between mGIC and Eva1-knockdown mGIC, we further found Eva1 signal pathway. Eva1 induced GIC proliferation through the activation of the RelB-dependent noncanonical NF-kB pathway by recruiting TRAF2 to the cytoplasmic tail. This signal pathway is important for human GBM formation. Taken together, these findings suggest that Eva1 is a potential target for immunotherapy. 

Biography:

Chunman Lee has his expertise in evaluation and passion in improving the antitumor efficacy of novel formulations against cancer dissemination. He started carrier as a surgeon at Osaka university hospital, and passed through the surgery program of Osaka university graduate school of medicine. Then he worked at University of Texas Southwestern Med. Ctr. at Dallas as a postdoctoral fellow. Now he researches the immunotherapy against pleural mesothelioma which is very refractory disease at Osaka university hospital as an associate professor. 

Abstract:

Hemagglutinating virus of Japan envelope (HVJ-E) developed from HVJ virus. HVJ was first discovered in Japan in 1950’s. It is mouse parainfluenza virus, not human pathogen. The virus has become very famous, since the discovery of virus-mediated cell fusion. Using the fusion activity of HVJ, a versatile drug delivery system mainly gene transfection was developed. Recently we discovered that HVJ-E possesses the various antitumor activities. One is enhancing antitumor immunities such as activation of dendritic cells, induction of natural killer cells and cytotoxicic T lymphocytes, and suppression of regulatory T cells. Other activities are direct tumor-killing by the induction of cell death through the RIG-I/MAVS pathway. We already finished phase I trial against melanoma and castration resistant prostate cancer. Then, we did the phase I dose escalation safety/tolerability and preliminary efficacy study of intra-tumoral and subsequent subcutaneous administration of HVJ-E to the patients suffering from chemotherapy–resistant pleural mesothelioma who had not receive chemotherapy in the last 4 weeks, had a performance status of 0-1, had certain functions of bone marrow, liver, kidney, and lung, had evaluable lesion with Computed Tomography and FDG-PET scan, had lesion which can be administrated with HVJ-E. Exclusion criteria is presence of autoimmune disease, interstitial pneumonia needed to treat, and other malignant lesions, use of systemic steroids, a protocol is consisted of initial-tumor administration of HVJ-E and the subsequent three subcutaneous administrations within two weeks, and then washed out for two weeks. This one cycle is repeated twice. Six patients were registered, and they were finished receiving this clinical trial. The adverse events were evaluated by independent data monitoring committee. We will show the data of AEs and antitumor efficacy of HVJ-E in this clinical trials.

Biography:

Nickolai Usachev has substantial practical expertise in cardiology and intensive care, combined with more than decade’s experience in the field of clinical studies. Since 2009 Dr.Usachev heads the Pharmacovigilance unit of PSI CRO.

Abstract:

Summarizing our experience of medical monitoring in clinical studies in patients with relapsed diffuse large B-cell lymphoma (DLBCL) pre-treated with standard Rituximab based scheme, we were surprised by a rather high incidence of increased Troponin T (TnT) in patients that had no detectable cardiac pathology. Such patients were screened out even if this lab finding was the only contraindication for inclusion. Purpose of the study: accumulate literature data confirming that in this particular group of patients mildly elevated TnT measured by immunoassay and not supported by any overt cardiovascular manifestations can be caused by reasons other than cardiovascular pathology. Therefore such patient can be included in the study and have potential benefit from treatment. Findings: about 10-11% of patient’s serum samples [1] may contain HAMA (human anti-mouse antibodies) [2], which lead to false positive results of troponin immunoassay [3; 4; 5]. Oncology patients, especially treated with monoclonal antibodies (Mab)–based immunotherapy are at significantly higher risk of HAMA development [2; 6; 7]. Available literature data suggest that quantitative measurement of HAMA in oncology patients has far more practical impact than simple confirmation of ambiguous immunoassay results. Survival benefit associated with HAMA in patients with B-cell malignancies [8] and with non-Hodgkin’s lymphoma treated with anti-lymphoma Mab [9; 10; 11] had been demonstrated.  Conclusion: HAMA measurement in potentially eligible patients who had previously received Mab immunotherapy and whose only contraindication for inclusion into the clinical study is mildly elevated TnT, seems justified. First, the patients with the false-positive TnT results caused by HAMA, will be included and may have potential benefits from study treatment. Second, the result of the HAMA test may have predictive value for treatment benefit.

Biography:

Guang-Yaw LIU, PhD., Professor, Institute of Biochemistry, Microbiology & Immunology, Chung Shan Medical University.

Abstract:

Peptidylarginine deiminase type 2 (PADI2) is a post-translational modification enzyme that catalyzes arginine residues into the citrulline residues. Previous studies have shown that PADI2 promotes protein citrullinations in lymphocytes and it might play an important role in cell-mediated inflammation. We have found that overexpression of PADI2 promotes apoptosis in activated T cells previously. Whether does PADI2 participate in the pathway of activated T cell autonomous death (ACAD) is still curious. In this delicate PADI2-mediated ACAD study, we found that overexpression of PADI2 displayed higher levels of citrullinated protein which would induce the ER stresses significantly. The high levels of citrullinated protein results in unfolding protein response (UPR) of ER stresses and increases the huge protein degradation loading. Autophagy might embrace the engulfment and degradation capacity of the citrullinated and unfolding proteins. Herein, PADI2 could enhance autophagy in Jurkat T cells and lead to a degradation of p62 and the accumulation of LC3-II, BCEN1, ATG5 and ATG12. Autophagy and apoptosis are two critical mechanisms both which participate against cellular stresses and decide T cell activation, survival and immuno-homeostasis. PADI2-overexpressed Jurkat T cells caused the activation of Th17 cells due to the increase mRNA expression of cytokines, such as IL-17, IL-21, IL-22 and TNFα. Cytokines declined autophagy, provoked caspase cascade expression, and led to ACAD by IL-6 shRNA inspection. Simultaneously, autophagic BCEN1 could reduce Bcl-xL expression, increase caspase cascade and cause to cell insults. Knockdown of BCEN1 possibly will rescue Jurkat T cell activation, increase cytokine release and induce ACAD. We suggested that PADI2 participated in the activated T cell-induced autonomous death through triggering ER stress pathway coupling with regulating autophagic processing, and stimulating Th17 activation and the expression of cytokines by PADI2-citrullinating mechanism.

Biography:

Hui-Chih Hung, Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, 

Abstract:

This study reveals a novel mechanism for the regulation of polyamine homeostasis through protein arginyl citrullination of antizyme (AZ), a natural inhibitor of ornithine decarboxylase (ODC). ODC is a tumor promoter and is critical for cellular polyamine production. AZ binds to ODC dimers and promotes the degradation of ODC via the 26S proteasome. This study demonstrates the protein citrullination of AZ catalyzed by peptidylarginine deiminase type 4 (PAD4) both in vitro and in cells. Higher levels of putrescine and citrullinated AZ proteins were observed in cells with PAD4 activation. The levels of ODC enzyme activity and protein increased with the level of citrullinated AZ proteins in PAD4-overexpressing cells. Our data also indicated that citrullinated AZ proteins have weaker binding affinities with ODC, greatly reducing the ability of citrullinated AZ protein to bind, inhibit, and promote the degradation of ODC. Based on LC-MS/MS analysis, eight citrullination sites of AZ were identified; Arg180 and Arg183 were identified as the critical citrullinated residues in AZ that impair the binding, inhibition, and degradation of ODC. This study is the first paper, to our knowledge, to demonstrate the post-translational modification of AZ by arginyl citrullination and reveals that AZ citrullination is involved in the up-regulation of cellular ODC and polyamines, strongly implying an association with cancer development.

Biography:

Dr. Liyan Song is currently a Professor of Pharmacology in Biotechnological Institute of Chinese Materia Medica, Jinan University, China. She has worked with cancer and immunology studies in the past years. Specially, she is interested in mechanism research involved in cell signaling pathways. Her research team is also engaged in the development of novel antitumor drug, and financially supported by several foundations including Major National Science and Technology Projects/Significant New Drugs Creation as well as National Natural Science Foundation of China.

Abstract:

Statement of the problem: Although standard therapeutic protocols for cancer have been improved, it is still imperative to investigate novel anti-tumor strategies for eliminating cancer cells with little toxicity to normal cells. It is generally accepted that natural polysaccharides are capable of immunomodulatory activities. As a traditional Chinese medicine, Cordyceps militaris is widely used for health supplement. This study aims to investigate the anti-tumor and immunomodulatory effects of Cordyceps militaris polysaccharide fraction (CMPF). Methodology & Theoretical Orientation: The mouse model of S180 sarcoma was established and the effect of CMPF on tumor weight, organ index, and cytokines were examined in S180-bearing mice. The effect of CMPF on carbon clearance ability and DTH reaction of immunosuppressive mice were also investigated. Additionally, the immunomodulatory effect of CMPF and the possible mechanism were studied in macrophages and splenic lymphocytes. Findings: CMPF had no effect on proliferation of S180 cells in vitro. However, it inhibited tumor growth, increased levels of cytokines TNF-alpha and IL-2, and improved spleen and thymus indexes in S180-bearing mice. When combined with 5-fluorouracil, CMPF exerted synergistic effect and reduced toxicity of 5-fluorouracil. Other in vivo experiment results showed that CMPF enhanced carbon clearance ability and DTH reaction of immunosuppressive mice. On the other hand, in vitro assays revealed that CMPF promoted proliferation of splenic lymphocytes and cytotoxicity of NK cells to YAC-1 cells. CMPF also increased secretion of IL-2, development of cell cycle toward S phase, as well as T cell subpopulation. The phagocytosis function of macrophages and secretion of both NO and TNF-alpha by macrophages were also promoted by CMPF. Conclusion & Significance: These results indicate that CMPF possesses immunomodulatory effect on multiple immune cells in vitro. CMPF exhibited anti-tumor effect in vivo probably via immunomodulation. CMPF could potentially be used as a functional supplement candidate for tumor therapy.