eSymposia | Advances in Cancer Immunotherapy - Student Rate



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Cancer stemness, intratumoral heterogeneity, and immune response across cancers

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Cancer stemness, intratumoral heterogeneity, and immune response across cancers

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Cancer stemness, intratumoral heterogeneity, and immune response across cancers. The exclusion of immune cells from the tumor microenvironment has been associated with poor prognosis in the majority of cancers. Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype (“stemness”) on the immunological properties of cancer has not been systematically explored. Using gene-expression–based metrics, we evaluated the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We found pervasive negative associations between cancer stemness and anticancer immunity. This occurred despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell intrinsic suppression of endogenous retroviruses and type I IFN signaling, and increased expression of multiple therapeutically accessible immunosuppressive pathways. Thus, stemness is not only a fundamental process in cancer progression but may provide a mechanistic link between antigenicity, intratumoral heterogeneity, and immune suppression across cancers. Our work suggests that targeting the stemness phenotype in cancer will promote immune cell infiltration and render tumors more responsive to immune control. Alex Miranda*1, Phineas T Hamilton*1, Allen W Zhang2,3,4, Swetansu Pattnaik5, Etienne Becht6, Artur Mezheyeuski7, Jarle Bruun8, Patrick Micke7, Aurélien De Reynies9, Brad H Nelson10, 11 1 Deeley Research Centre, BC Cancer, Victoria, BC, V8R 6V5, Canada 2 Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada 3 BC Children's Hospital Research, Vancouver, BC V5Z 4H4, Canada 4 Graduate Bioinformatics Training Program, University of British Columbia, Vancouver, BC V6T 1Z3, Canada 5 The Kinghorn Cancer Centre and Cancer Division, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, NSW, Australia. 6 Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 7 Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 751 85, Sweden 8 Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Ullernchausseen 70, 0379 Oslo, Norway 9 Programme "Cartes d'Identité des Tumeurs" (CIT), Ligue Nationale Contre le Cancer, 14, rue Corvisart, 75013, Paris, France. 10 Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8P 3E6, Canada 11 Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. * These authors contributed equally to this work

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A Novel Cell-Mediated Immunotherapy for Treatment of Lung and Breast Cancer

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A Novel Cell-Mediated Immunotherapy for Treatment of Lung and Breast Cancer

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

A Novel Cell-Mediated Immunotherapy for Treatment of Lung and Breast Cancer Title: A novel cell-mediated immunotherapy for treatment of lung and breast cancer Main author: Indu Venugopal Co-Authors: Claire Gormley[1]; Michael J. McGuire[1]; Kathlynn C. Brown[1] Co-Authors' Institutions: [1] Biological Sciences Division, SRI International, 140 Research Drive, Harrisonburg, VA 22802 USA Abstract: Cell-mediated (CM) cancer immunotherapies are now generating effective treatments for several cancers which were previously thought to be untreatable. Major examples include Dendritic Cell vaccines, PD-1 and CTLA-4 inhibitors, injection of live or attenuated virus into tumors, and adoptive T-cell therapies. The principle of most CM immunotherapies is simple - to activate the body’s adaptive immune system to generate a cytotoxic T lymphocyte response against tumor antigens, resulting in the elimination of the tumor. However, the complexity of the tumor micro-environment and adverse side effects make it extremely difficult to harness the specificity of the immune system for tumor treatment. Also, concerns regarding cost, efficacy and safety have impeded their development into effective clinical therapies. To address these weaknesses, we have developed a novel immunotherapy capable of delivering previously encountered antigenic peptides specifically to cancer cells and facilitating their presentation through the MHC class I pathway. Our therapy utilizes a synthetic nanoparticle delivery system comprising of three components: a neutral stealth liposome, encapsulated synthetic immunogenic HLA class I restricted peptides derived from measles virus (MV), and a tumor-targeting peptide on the external surface of the liposome. The targeting peptide results in accumulation of the liposomes specifically inside cancer cells, and facilitates presentation of the MV-derived immunogenic peptides specifically in HLA class I molecules. We refer to this system as TALL (Targeted Antigen Loaded Liposomes). Therefore, TALL can generate a secondary immune response specifically against the targeted tumor cells in a patient who has been previously vaccinated against or infected by MV. In short, we are attempting to trick the immune system into responding as though the cancer cell is infected with MV without the use of a viral particle. To prove this concept, we synthesized a liposome encapsulating H250, an immunogenic HLA class I restricted peptide identified from measles hemagglutinin protein. These liposomes were targeted specifically to breast and lung cancer cells via our targeting peptide, which was identified using phage-display methodology. Treatment of lung cancer cells with TALL results in functional presentation of H250 in both MHC and HLA class I molecules. Our in vitro and in vivo studies indicate that presentation of H250 is dependent on the cancer targeting peptide; liposomes that lack the targeting peptide did not accumulate in the cancer cells and presentation of H250 was abrogated. We have shown that treatment with TALL substantially reduces growth of LLC1(lung) and 4T1(triple-negative breast) tumors in vaccinated C57BL/6 and Balb/c mice respectively, compared to vehicle treatment. As TALL can provide a potent synthetic antigen specifically to tumor cells, it can turn immune-cold tumors into immune-hot tumors, which is capable of eliciting a strong immune response. We have therefore conducted a pilot study to determine the efficacy of combining TALL with checkpoint inhibitors to reduce the tumor burden in mice bearing orthotopic 4T1 tumors. Checkpoint inhibitors are known to be far less efficacious in immune-cold tumors such as triple negative breast cancer. The results of the study indicated a significant reduction in the tumor burden of mice treated with the combination therapy compared to when either treatment is used alone. The outcome of our TALL treatment is a robust cytotoxic T lymphocyte response directed specifically against the tumor. This approach has advantages over current immunotherapies: 1) It bypasses the need to identify tumor-associated antigens or educate the immune system through a primary immune response; 2) It is anticipated to be effective against tumors with a low mutational load, making it efficacious on early stage as well as metastatic cancer; 3) It does not use live virus, viral subunits or biologically derived material, allowing for complete synthetic manufacturing. It also does not require isolation, culture, or ex vivo manipulation of patient’s cells, which reduces production time and costs.

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Developing oxidative stress-resistant CAR-T for solid tumors

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Developing oxidative stress-resistant CAR-T for solid tumors

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Developing oxidative stress-resistant CAR-T for solid tumors Allison J Nipper1, Emilie AK Warren1, Caroline E Porter2,3, Tim Sauer3, Mariana Villanueva1, Hugo Villanueva1, Masataka Suzuki2,3, Andrew G Sikora1,4 1Department of Otolaryngology, Baylor College of Medicine, Houston, TX 2Department of Medicine; BCM 3Center for Cell and Gene Therapy, BCM; 4Department of Head and Neck Surgery, MD Anderson, Houston TX High levels of oxidative stress in the solid tumor microenvironment inflict cellular damage and alter functionality of tumor infiltrating lymphocytes. The hostile environment of solid tumors therefore poses a challenge to immunotherapy, which moderates the action of immune cells to combat tumor growth. As a result, T cells transduced with Chimeric Antigen Receptors (CAR-T) for solid tumors have not shown the success observed for leukemia and lymphoma. To combat the effect of oxidative stress on tumor-specific T cells, we have developed a novel approach to CAR-T protection by incorporating the damage suppressor (Dsup) gene from the “extremotolerant” organism the tardigrade. Tardigrades show extreme oxidative stress resistance to alleviate cellular damage during desiccation. Therefore, we hypothesize that transgenic expression of tardigrade oxidative stress response proteins in CAR-T will enhance their survival and function in solid tumors and will mitigate effects of stress on anti-tumor response. To this end, we have generated CAR-T expressing tardigrade oxidative stress response gene Dsup to explore their functionality in solid tumor environments. To determine if Dsup enhanced T cell survival under metabolic stress, we transduced primary T cells with tardigrade stress response gene Dsup or a vector only control. When cultured with H2O2 to generate oxidative stress, T cells transduced with Dsup have greater viability than T cells receiving only the control vector. To determine if the expression of Dsup affected the anti-tumor efficacy of CAR T we cocultured HER2 CAR-T with and without Dsup for 48 hours with HER2-expressing FaDu tumor cells, then quantified tumor cell death by flow cytometry. In preliminary data, we observed HER2-specific CAR-T with Dsup to kill tumor cells in culture. To determine if Dsup improves CAR-T ability to target or kill cells in vivo, CAR-T transduced with antioxidant gene Dsup were used to treat FaDu tumors grown in the chick chorioallantoic membrane model. After treatment with Dsup-HER2.CAR-T, tumors were harvested for analysis, at which time T cell infiltrates were seen throughout the tumor in 3D reconstructions generated by confocal microscopy. Together, this work suggests antioxidant genes have potential to enhance CAR-T efficacy in solid tumors through oxidative stress protection.

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Kras is essential to the immunosuppressive tumor microenvironment in colon cancer via regulation of pioneer transcription factors

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Kras is essential to the immunosuppressive tumor microenvironment in colon cancer via regulation of pioneer transcription factors

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Kras is essential to the immunosuppressive tumor microenvironment in colon cancer via regulation of pioneer transcription factors Colorectal cancer (CRC) is the second leading cause of cancer death in the United States and is particularly deadly if diagnosed at late stage. The vast majority of colon cancers are sporadic with a stereotypical pattern of accumulated mutations. The initiating event in sporadic colon cancer is a loss-of-function mutation in adenomatous-polyposis coli (APC), followed by the mutation of p53 and an activating mutation in the oncogene KRAS. KRAS is one of the most frequently mutated oncogenes in cancer and is a predictive biomarker of therapeutic response. In order to investigate how mutational burden in colon cancer regulates the immune microenvironment and cancer metabolism, three separate murine models were assessed using a multi-omics approach. We have established a mouse model of colon carcinogenesis with i) Apcloss, ii) expression of mutant KrasG12D, iii) homozygotic deletion of p53 iv) using a tamoxifen-inducible Cre line that is only expressed in the colon epithelial cells (Cdx2ER-Cre). We refer to these mice as the TripleMutmice. We also utilized the Apc deletion mouse model, denoted SingleMut, and an Apc and a p53 homozygous deletion, denoted DoubleMut. Kras mutation in the TripleMutresults in a more aggressive and invasive phenotype, higher colon tumor burden, and metastasis to the liver and the lung. Consistent with the enhanced tumor progression, increased mutational burden leads to decrease survival. In addition, the TripleMutmice are resistant to anti-IL17 or PD-L1 neutralizing antibody whereas SingleMutand DoubleMutmice are responsive to both immune based therapies. I employed a multi-omics approach with mass cytometry (CyToF) and RNA-SEQ to understand how KRAS mutation alters the immune infiltrate. CyToF is a high-throughput flow-based technique using simultaneous metal labeling of up to 50 antibody markers (21). The TripleMutmice have a decrease in anti-tumor inflammatory pathways and infiltration of activated T-cells compared to the DoubleMutmice. This data suggests KRAS mutation modulates an immunosuppressive microenvironment. Network analysis of the RNA-SEQ data shows that the genes differentially expressed between the DoubleMutand TripleMutprimarily belong to three families: the Polycomb Repressor Complex 2 (PRC2), STAT/IRF signaling, Wnt/beta-catenin signaling, and HNF4A. We found that human colon cancer cell lines are highly sensitive to PRC2 inhibitors, and plan to use chemical and genetic approaches to inhibit all three of these main pathways in the TripleMutmice as a potentially combinatorial therapy.

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Histone Deacetylase Inhibition Sensitizes PD1 Blockade–Resistant B-cell Lymphomas

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Histone Deacetylase Inhibition Sensitizes PD1 Blockade–Resistant B-cell Lymphomas

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Histone Deacetylase Inhibition Sensitizes PD1 Blockade–Resistant B-cell Lymphomas Xiaoguang Wang1, Brittany C.Waschke1, Rachel A.Woolaver1, Zhangguo Chen1, Gan Zhang2, Anthony D. Piscopio3, Xuedong Liu2,3, and Jing H.Wang1,* 1Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. 2Department of Biochemistry, University of Colorado Boulder, Boulder, Colorado. 3OnKure Inc., Boulder, Colorado. *Correspondence author PD1-blockade is effective in a subset of B cell lymphoma patients (e.g., classical-Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To overcome PD1-resistance, we employ a newly developed isoform-selective histone-deacetylase-inhibitor (HDACi) (OKI-179), and a novel mouse mature B cell lymphoma, G1XP lymphoma, that resembles immunosuppressive features of human B cell lymphomas including downregulation of major histocompatibility complex (MHC) class I and II, exhaustion of CD8 and CD4 tumor infiltrating lymphocytes (TILs), and PD1-blockade resistance. Using multiple lymphoma models, we show that combined treatment of OKI-179/anti-PD1 significantly inhibited growth of B cell lymphomas refractory to PD1-blockade; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated to MHC class II level. We conclude that OKI-179 sensitizes lymphomas to PD1-blockade by enhancing tumor immunogenicity. Additionally, we found that different HDACi exhibited distinct effects on tumors and T cells, yet, the same HDACi could differentially affect HLA expression on different human B cell lymphomas. Thus, our study highlights the importance of immunological effects of HDACi on anti-tumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and unique profiles of HDACi.

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  • Jing Wang, MD, PhD, University of Colorado Anschutz Medical Campus

MerTK blockade enhances innate immune sensing of tumors and antitumor response

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MerTK blockade enhances innate immune sensing of tumors and antitumor response

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

MerTK blockade enhances innate immune sensing of tumors and antitumor response Tissue macrophages dispose apoptotic cells via a phagocytic process termed efferocytosis. Unpunctual removal of dying cells increases the production and release of molecules with immune stimulatory activities. MerTK-expressing tumor-associated macrophages (TAMs) may employ the same clearance mechanism to minimize host immune recognition of dying cancer cells. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Further mechanistic studies revealed that the type I interferon response was driven by STING transactivation in immune cells by cGAS in tumor cells. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1/PD-L1 therapy. Our findings provide insights into harnessing phagocytic clearance of dying cells to increase tumor immunogenicity and improve cancer immunotherapy.

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Liquid Biopsy Protein Biomarkers to Predict Responses and Elucidate Resistance to Cancer Immunotherapy in Metastatic Melanoma

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Liquid Biopsy Protein Biomarkers to Predict Responses and Elucidate Resistance to Cancer Immunotherapy in Metastatic Melanoma

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Liquid biopsy protein biomarkers to predict responses and elucidate resistance to cancer immunotherapy The response of metastatic melanoma to anti-PD1 is heterogeneous. We performed proteomic profiling of patient plasma samples to build a predictor of immunotherapy response and uncover biological insights underlying primary resistance. An initial cohort comprised 55 metastatic melanoma patients receiving anti-PD1 (Pembrolizumab or Nivolumab) at Massachusetts General Hospital (MGH), and 116 additional patients comprised a validation cohort. Plasma samples were collected at baseline and on-treatment, at 6 weeks and 6 months’ time-points, and profiled for 1000 proteins by a multiplex Proximity Extension Assay (PEA, by Olink Proteomics). A subset of patients had single-cell RNA-seq (Smart-Seq2 protocol) performed on tumor tissue. Group differences and treatment effects were evaluated using linear mixed models with maximum likelihood estimation for model parameters, and Benjamini and Hochberg multiple hypothesis correction. At the baseline, 6 differentially expressed proteins were identified between responders (R) and non-responders (NR) whereas immune suppression marker ST2 and IL-6 were found significantly higher among NR. Kaplan-Meier survival curves stratified by the baseline differentially expressed proteins were highly predictive of overall survival (OS) and progression-free survival (PFS). At 6-weeks on-treatment time point, 80 proteins were found differentially expressed between R and NR including several proteins implicated in primary or acquired resistance (IL8, MIA, TNFR1 among others). Several 6-weeks differentially expressed proteins were highly predictive of survival (ICOSL, IL8, MIA). Furthermore, 160 significantly differentially expressed (DE) proteins were identified across the treatment period majority of which are reflective of immune activation under the pressure of the immunotherapy. Analysis of single-cell RNA-seq data of tumor tissue from a subset of these patients revealed that gene expression of most proteins predictive of response were enriched among tumor myeloid cells, with the remainder of proteins being reflective of exhausted T cell states. These results unveil a putative role of myeloid cells within the tumor microenvironment in anti-PD1 response or primary resistance. Whole plasma proteomic profiling of anti-PD1 treated patients revealed DE proteins between R and NR that may enable a liquid biopsy to predict anti-PD1 response. Importantly, we demonstrate the relationship of serum biomarkers to OS and PFS and are currently attempting to build machine learning classifiers as predictors of response to checkpoint therapy leveraging early and late on-treatment time points.

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CUE-102 Immuno-STATs for selective targeting and expansion of WT1-specific T cells for the treatment of cancer patients expressing WT1

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CUE-102 Immuno-STATs for selective targeting and expansion of WT1-specific T cells for the treatment of cancer patients expressing WT1

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

CUE-102 Immuno-STATs for selective targeting and expansion of WT1-specific T cells for the treatment of cancer patients expressing WT1 Histed A., Girgis N., Moreta M., Soriano J., Witt L., Merazga Z., Diaz F., Zhao F., Kemp M., Ruthardt P., Thapa D., Suri A., Quayle S., Ross J., Cemerski S. WT1 has been ranked first amongst 75 tumor associated antigens in an effort by the National Cancer Institute to prioritize cancer antigens for therapeutic targeting. Development of novel modalities to target WT1 provide a significant opportunity to address high unmet medical need in WT1-positive malignancies, including AML, ovarian, endometrial, breast, lung, colorectal and pancreatic cancer. We have developed, in partnership with LG Chem, two novel fusion proteins, termed Immuno-STATs (Selective Targeting and Activation of T cells), that are comprised of HLA-A*02 or HLA-A*24 molecules (human leukocyte antigen) presenting peptide epitopes derived from WT1. Each CUE-102 Immuno-STAT molecule also contains four copies of affinity-attenuated human interleukin-2 (IL-2), and an effector attenuated human immunoglobulin G (IgG1) Fc domain. We present here the biochemical characterization of the CUE-102/A02 Immuno-STAT and its bioactivity across a variety of in vitro and in vivo studies. CUE-102/A02 Immuno-STAT presents the WT137-45 peptide in the context of HLA-A*02, and selectively targets and activates WT137-45-specific CD8+ T cells. Signaling, cell-based assays and cytokine release studies confirmed significant functional attenuation of the IL-2 components of CUE-102. Primary stimulation of unprimed hPBMCs, or re-stimulation of hPBMCs after initial WT1 peptide stimulation, led to robust expansion of WT137-45 -specific CD8+ T cells and demonstrated the ability of the CUE-102/A02 Immuno-STAT to stimulate and expand WT137-45 antigen-specific T cells from both unprimed and pre-primed T cell repertoires. CUE-102/A02 also expanded a population of WT137-45-specific CD8+ T cells upon administration to naïve HLA-A*02 transgenic mice. In both cases the expanded T cells exhibited a polyfunctional response upon challenge with WT137-45-presenting target cells. The repertoire of the expanded cells, their polyfunctionality and ability to recognize and respond to WT1 peptide-presenting target cells suggest that CUE-102 Immuno-STATs have the potential to enhance anti-tumor immunity in patients with WT1-positive malignancies.

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Megakaryoblastic Leukemia: A Study on Novel Role of Clinically Significant Long non-coding RNA Signatures in megakaryocyte development and immune regulation during Treatment with Phorbol Ester

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Megakaryoblastic Leukemia: A Study on Novel Role of Clinically Significant Long non-coding RNA Signatures in megakaryocyte development and immune regulation during Treatment with Phorbol Ester

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Megakaryoblastic Leukemia: A Study on Novel Role of Clinically Significant Long non-coding RNA Signatures in megakaryocyte development and immune regulation during Treatment with Phorbol Ester Ravi Kumar Gutti* and Swati Dahariya Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad-500046 (TS), India. *E-mail: guttiravi@gmail.com Background: Treatment of hematopoietic cells with phorbol esters, such as phorbol 12-myristate 13-acetate (PMA), causes them to undergo differentiation to more mature cell types. Dami cell line differentiates into megakaryocyte-like cells. The ability of phorbol esters to induce differentiation of leukemic cells suggests that these can be used for the treatment of human leukemia. PMA-induced differentiation regulates several proteins that are essential for megakaryocytopoiesis through long-non-coding RNAs (lncRNAs) mediated regulation. Several studies show that lncRNAs play important role in the biological processes, including differentiation and development of the blood cells. However, lncRNA expression has not yet been comprehensively characterized in megakaryocytes (MKs). Method: Megakaryoblastic cell line Dami (ATCC Cat # CRL-9792) are derived from the peripheral blood of a patient with megakaryoblastic leukaemia and these cells provide perfect model to study the process of megakaryopoiesis. These cells were grown in RPMI-1640 medium supplemented with 10% FBS and 1% antibiotic-anti mycotic (Invitrogen). We created an inducible system that utilizes a versatile chemical PMA. We collected cultures expressing high CD41+ by flow cytometry. Total RNA was isolated after 7 days of PMA (100 nM) treatment using Qiagen RNeasy Mini kit using manufacturer instructions and cDNA was prepared which was further used for profiling Human LncRNAs using Profiler qPCR Array kit. Result: In this study, we found that PMA-induced differentiation induces expression of several lncRNAs, and was significantly associated with different stages of MK development. The analysis showed that 48 of 91 detected lncRNAs demonstrated significant >2-fold differential expression in response to treatment with PMA for 7 days. Among them, when the cut-off was set to 4-fold, we recognized 12 lncRNAs showing up-regulated significantly, while 2 lncRNAs were significantly down-regulated in mature MKs on day 7 when compared to dami on day 0. The significantly up-regulated 12 lncRNAs are BACE1AS (family), DISC2 (family), H19 upstream conserved 1 & 2, HOXA6as, IGF2AS (family), Malat1, NDM29, NEAT1 (family), PSF inhibiting RNA, PTENP1, SNHG5, UCA1. Furthermore, the down-regulated lncRNAs are Dio3os (family) and HOXA3as. I Conclusion: Our results suggest a differential expression of lncRNAs upon PMA treatment and their involvement in MK biology.

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MiRNA-Modified Coxsackievirus B3 (CVB3) for Treating Lung Cancer

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MiRNA-Modified Coxsackievirus B3 (CVB3) for Treating Lung Cancer

Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

MiRNA-Modified Coxsackievirus B3 (CVB3) for Treating Lung Cancer Huitao Liu,1,7 Yuan Chao Xue,1,2 Haoyu Deng,1,2,3 Yasir Mohamud,1,2 Chen Seng Ng,1,2 Axel Chu,4 Chinten James Lim,4 William W. Lockwood,2,5 William W.G. Jia,6 and Honglin Luo1,2,7 1 Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada; 2 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; 3 Department of Vascular Surgery, RenJi Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; 4 Department of Pediatrics, University of British Columbia, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; 5 Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada; 6 Department of Surgery, Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada; 7 Department of Experimental Medicine, University of British Columbia, Vancouver, BC, Canada We recently discovered that coxsackievirus B3 (CVB3) is a potent oncolytic virus against KRAS mutant lung adenocarcinoma. Nevertheless, the evident toxicity restricts the use of wild-type (WT)-CVB3 for cancer therapy. The current study aims to engineer the CVB3 to decrease its toxicity and to extend our previous research to determine its safety and efficacy in treating TP53/RB1 mutant small-cell lung cancer (SCLC). A microRNA-modified CVB3 (miR-CVB3) was generated via inserting multiple copies of tumor-suppressive miR-145/miR-143 target sequences into the viral genome. In vitro experiments revealed that miR-CVB3 retained the ability to infect and lyse KRAS mutant lung adenocarcinoma and TP53/RB1-mutant SCLC cells, but with a markedly reduced cytotoxicity toward cardiomyocytes. In vivo study using a TP53/RB1-mutant SCLC xenograft model demonstrated that a single dose of miR-CVB3 via systemic administration resulted in a significant tumor regression. Most strikingly, mice treated with miR-CVB3 exhibited greatly attenuated cardiotoxicities and decreased viral titers compared to WT-CVB3-treated mice. Collectively, we generated a recombinant CVB3 that is powerful in destroying both KRAS mutant lung adenocarcinoma and TP53/RB1-mutant SCLC, with a negligible toxicity toward normal tissues. Future investigation is needed to address the issue of genome instability of miR-CVB3, which was observed in ~40% of mice after a prolonged treatment.

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