bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1674: WNT signal pathway activation correlates with innate resistant to immune checkpoint therapies in melanoma
Authors: Gong Fuyu , Bai Yuezong , Xie wenzhuan , Cui Chuanliang 
Published: July 2021

Abstract
Background: Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with melanoma. There are still lots of patients could not reach the clinical benefit, even though with the positive expression of the programmed cell death 1 ligand 1 (PD-L1). Here, we aimed to research the immune resistance mechanism in melanoma.
Methods: The genomic data and clinical data of the discovery cohort was obtained from The Cancer Genome Atlas (TCGA). The clinical data of validation cohort in melanoma treated by immunotherapy was retrospective collected. And tissue from patients with melanoma were performed to whole exome sequencing in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab.
Results: Activation of WNT signaling was inferred that somatic mutations or somatic copy number alterations in WNT signaling elements including APC, WNT1, WNT4, WNT6, WNT16, CTNNB1, BCL9L, SMAD3 and SMAD4. Two cohort have been enrolled in this study, the discovery cohort from TCGA, and the validation cohort from the Chinese patients with melanoma. The frequency of WNT pathway alterations from the TCGA cohort was 28.4%, and which was represented mutually exclusive molecular subsets. In TCGA cohort, activating alteration WNT signaling were associated with shorter median OS (22.5 vs 13.6 months, p=0.047, HR=0.61 (0.37-0.89)).
Conclusions: Mutations predicted to activate the WNT pathway were associated with innate resistance to immune checkpoint blockade in melanoma.
Citation Format: Fuyu Gong, Yuezong Bai, wenzhuan Xie, Chuanliang Cui. WNT signal pathway activation correlates with innate resistant to immune checkpoint therapies in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1674.
Abstract 1679: Innate immunity and cytokine signaling pathways drive resistance to HSV-1 oncolytic immunovirotherapy in glioblastoma
Authors: Monie Dileep D. , Correia Cristina , Zhang Cheng , Ung Choong , Vile Richard G. , Li Hu 
Published: July 2021

Abstract
Glioblastoma multiforme (GBM) is a particularly aggressive primary brain tumor that is relatively common in adults. The disease comes with a dismal prognosis, often with expected survival just over a year when treated with surgery, chemotherapy, and radiation. A promising addition to our GBM treatment arsenal are oncolytic viruses (OVs), a class of immunotherapy now in clinical trials. The most effective OVs home in on tumor cells, killing them and releasing tumor-associated antigens that elicit antitumor immunity. This effectiveness, however, varies depending on the cell state—a property that may be influenced by the composition of the extracellular matrix (ECM) of GBM. Cellular communication network factor 1 (CCN1) is found in the ECM of the majority of GBMs and is predictive of resistance to OVs, particularly those derived from herpes simplex virus type 1 (HSV-1). In this study, our aim is to understand how extracellular CCN1 alters the GBM intracellular state in a manner that confers resistance to OVs. We began by using our NetDecoder platform to build CCN1-specific prioritized protein-protein interaction (PPI) networks from published LN229 human GBM transcriptomic datasets. From this network, we identified 12 PPI edges that dominate the network flow in CCN1-high LN229 cells when compared to CCN1-low controls. The 21 unique nodes that comprise these binary PPI edges were extracted and subjected to downstream biological process overrepresentation analyses using Gene Ontology. We found that the cytokine-mediated signaling pathway (FDR = 4.2 x 10-11; enrichment ratio = 15.8) and the cellular response to cytokine stimulus (FDR = 3.1 x 10-9; enrichment ratio = 10.9) were highly enriched when mapped to these nodes. We conclude that CCN1, acting as a paracrine signal in the GBM tumor microenvironment, primes the cell to inhibit HSV-1 and other candidate OV replication prior to any virus interactions, thus contributing to immunovirotherapy resistance. While CCN1 and its cell surface integrin binding partners are ostensible drug targets for overcoming this resistance, pharmacologic interventions that target CCN1-specific high flow edges in our prioritized PPI network may be more effective.
Citation Format: Dileep D. Monie, Cristina Correia, Cheng Zhang, Choong Ung, Richard G. Vile, Hu Li. Innate immunity and cytokine signaling pathways drive resistance to HSV-1 oncolytic immunovirotherapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1679.
Abstract 1687: T cells are required to maintain anti-CD20-mediated NK cell responses in vitro
Authors: Wang Zhaoming , Weiner George J. 
Published: July 2021

Abstract
Purpose: Anti-CD20 monoclonal antibodies, beginning with rituximab (RTX), are a mainstay of therapy for B cell malignancies. Despite their remarkable clinical efficacy, many patients fail to respond or develop resistance to anti-CD20 containing therapy. A better understanding of the mechanisms by which anti-CD20 antibodies mediate their anti-tumor effects is critical if we are to build further on what is already a remarkable success story.
Experimental procedures: Various subsets of healthy donor peripheral blood mononuclear cells (PBMCs) were cocultured in vitro with Raji cells and RTX or trastuzumab (TRA) as a control antibody for up to 7 days. The number of remaining Raji cells, NK cells and phenotype of NK cells was determined.
Results: When unfractionated PBMCs were cultured with Raji cells for 1 week, RTX depleted Raji cells and enhanced NK cell numbers compared to TRA. In such cultures, RTX also induced changes in NK cell phenotype including a shift from CD56dim to CD56bright and increased expression of CD16, CD57 and KIR. These changes were dependent on T cells. Depletion of T cells, largely CD4, suppressed elimination of Raji cells, NK cell viability and the change in NK cell phenotype. Cell to cell contact was required, as the ability of T cells to support NK cell cytotoxicity, viability and phenotypic change was lost when T cells were separated from other cells in a transwell assay. T cell activation with anti-CD3/CD28 beads enhanced the ability of T cells to support RTX-mediated NK cell responses, with concentrations of activated T cells as low as 1% being adequate to provide T cell help to NK cells. Similar results were seen when obinutuzumab was used instead of RTX and when autologous B cells were used as target cells instead of Raji cells demonstrating the observed T cell effect was not secondary to an allogenic response by T cells to Raji cells.
Conclusion: In longer term in vitro culture, anti-CD20 induces lysis of target B cells, preserves NK cell viability, and induces CD56dim to CD56bright transition and CD16 recovery in a T cell dependent manner. This T cell help requires cell-to-cell contact with NK cells and is enhanced following T cell activation. Ongoing studies are exploring the precise mechanisms by which T cells support NK cells, and whether similar changes are observed in patients. These findings could lead to evaluation of a combination of anti-CD20 therapy and T cell activation as a strategy for overcoming resistance to anti-CD20 therapy.
Citation Format: Zhaoming Wang, George J. Weiner. T cells are required to maintain anti-CD20-mediated NK cell responses in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1687.
Abstract 1691: CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation
Authors: Otano Itziar , Azpilikueta Arantza , Glez-Vaz Javier , Ellmark Peter , Fritzell Sara , Fernandez-Hoyos Gabriela , Nelson Michelle Hase , Alvarez Maite , del Carmen Ochoa María , Bolaños Elixabet , Cuculescu Doina , Jauregui Patricia , Sanchez Sandra , Etxeberría Iñaki , Rodriguez-Ruiz María E. , Sanmamed Miguel F. , Teijeira Alvaro , Berraondo Pedro , Melero Igancio 
Published: July 2021

Abstract
CD137 (4-1BB, TNFSFR9) costimulation provides antigen-primed T cells with increased survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being harnessed for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cells is far superior to that provided in-trans in terms of T-cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mice and humans. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell-cycle and DNA damage repair gene expression programs. Superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which provide costimulation either in cis or in trans.
Citation Format: Itziar Otano, Arantza Azpilikueta, Javier Glez-Vaz, Peter Ellmark, Sara Fritzell, Gabriela Fernandez-Hoyos, Michelle Hase Nelson, Maite Alvarez, María del Carmen Ochoa, Elixabet Bolaños, Doina Cuculescu, Patricia Jauregui, Sandra Sanchez, Iñaki Etxeberría, María E. Rodriguez-Ruiz, Miguel F. Sanmamed, Alvaro Teijeira, Pedro Berraondo, Igancio Melero. CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1691.
Abstract 1692: A novel immunoregulatory role of tumor treating fields (TTFields) on macrophage polarization
Authors: Brant Boris , Voloshin Tali , Volodin Alexandra , Koren Lilach , Klein-Goldberg Anat , Zemer-Tov Efrat , Paz Rom , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: July 2021

Abstract
Introduction: Tumor Treating Fields (TTFields) therapy is a clinically applied anti-neoplastic treatment modality delivered via noninvasive application of low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. In this study we investigated the potential of TTFields for regulating macrophage phenotype skewing, with or without lipopolysaccharide (LPS) and interferon-γ (IFN-γ) or IL-4 activation.
Methods: Bone marrow cells were flushed from the femurs and tibias of 5-8 week old Balb\C mice to generate bone marrow-derived macrophages (BMDMs). To study individual macrophage responses to TTFields, we profiled macrophages that were stimulated with LPS+IFN-γ (M1 polarization) or IL-4 (M2 polarization), followed by treatment with TTFields (150 kHz) for 24 hours. Flow cytometry was used to assess surface expression of F4/80 (a macrophage biomarker) and the activation markers that included major histocompatibility complex class II (MHC II), CD80, and inducible nitric oxide synthase (iNOS). A multiplexed secretion assay was used to measure the heterogeneity of the stimulated macrophages. We captured the secretion of 13 different proteins including CXCL1 (KC), IL-18, IL-23, IL-12p70, IL6, TNF-α, IL-12p40, free active TGF-β1, CCL22 (MDC), IL-10, IL-6, G-CSF, CCL17 (TARC) and IL-1β.
Results: TTFields treatment polarized IL-4 stimulated M2 macrophages to the M1 phenotype, as indicated by a significant increase in the percentage of CD80+MHC IIhigh cells. Treatment with TTFields of BMDMs that were either stimulated with IFN-γ and LPS (M1 phenotype) or had remained unstimulated increased the percentage of CD80+MHC IIhigh cells to a lesser degree. Moreover, treatment with TTFields significantly increased intracellular iNOS levels in M1 polarized BMDMs. In unstimulated BMDMs, application of TTFields resulted in significant increases in secretion of the pro-inflammatory cytokines CXCL1, IL-18, IL-23, IL-12p70, TNF-α, IL-12p40, CCL22, G-CSF, CCL17 and IL-1β. Also, a similar pattern was observed in cell supernatants of M1 and M2 stimulated BMDMs after TTFields application.
Conclusions: These results elucidate a novel immunoregulatory role of TTFields on macrophage polarization. Future studies will aim to focus on the mechanism governing phenotypic skewing of macrophages treated with TTFields and to explore the effect of TTFields on macrophage in the tumor microenvironment.
Citation Format: Boris Brant, Tali Voloshin, Alexandra Volodin, Lilach Koren, Anat Klein-Goldberg, Efrat Zemer-Tov, Rom Paz, Moshe Giladi, Uri Weinberg, Yoram Palti. A novel immunoregulatory role of tumor treating fields (TTFields) on macrophage polarization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1692.
Abstract 1696: Anti-tumor effects from simultaneous cancer and TAM targeting by 010DS-Zn
Authors: Chung Jinhyuk Fred 
Published: July 2021

Abstract
Direct clearance of immune-suppressive Tumor Associated Macrophages (TAM) is a less-explored cancer therapeutic approach. We developed a novel folate-ligand guided zinc-peptide complex 010DS-Zn for selective induction of parthanatos in folate receptor overexpressing targets that include many solid and blood cancer types, in addition to M2-like macrophages. Consistent with known parthanatos mechanism, its in vitro mode-of-action (MOA) tested against 4T1 murine breast cancer cell was characterized by specific and rapid PARP-dependent AIF translocation into nucleus that executed massive DNA fragmentation. This in vitro/ex vivo cytotoxicity was found highly consistent against the 90 blood and solid patient-derived cancer types tested. Further in vivo MOA studies against aPD-1 responder and non-responder syngenic cancer models showed 010DS-Zn to be effective against both, albeit at increased dosage in the MDSC enriched tumors. In the aPD-1 responder cancer model CT26, 010DS-Zn demonstrated robust T-cell immune response initiation, which was enhanced upon co-treatment with aPD-1 mAb. Regardless of the tumor-response in vivo, 010DS-Zn treatment produced robust TAM-reduction activity in dose-dependent manners. Collectively, 010DS-Zn presents new cancer immunotherapeutic potentials for enabling previously inaccessible 2-combination therapies for targeting 3 layers of immune-evasion: Tregs, TAM, and MDSC. Furthermore, its ability to directly clear M2-like macrophages presents opportunities-worth-investigation for treating the M2-like macrophage-driven severe SARS-CoV-2 autoimmune syndromes or its post-recovery heart-damages.
Citation Format: Jinhyuk Fred Chung. Anti-tumor effects from simultaneous cancer and TAM targeting by 010DS-Zn [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1696.
Abstract 1698: Cardiovascular adverse events associated with immune checkpoint blockade: analysis of FDA-adverse events database
Authors: Castrillon Jessica A. 
Published: July 2021

Abstract
Background: Modern therapies in oncology have increased cancer survivorship, as well as the incidence of de novo cardiovascular events. While immune checkpoint inhibitors have shown significant clinical impact in several cancer types, the frequency of immune related adverse events is common.
Methods: We performed big data analytics on the FDA Adverse Events Reporting data of immunotherapy compared to chemotherapy adverse cases from January 2010- March 2020. We identified 90, 740 adverse event reports in both treatment groups. Myocarditis was significantly associated with patients receiving anti-PD-(L)1, 23.86 (95% CI 11.76-48.42, P &lt; 0.001) and combination immunotherapy, 7.29 (95% CI 1.03- 51.89, P &lt; 0.001). Myocarditis was most common in non-small cell lung cancer, melanoma, and renal cell carcinoma. Heart failure was significantly associated in chemotherapy compared to PD-(L)1, 0.50 (95% CI 0.37- 0.68, P &lt; 0.001), CTLA4, 0.08 (95% CI 0.03-0.20, P&lt;0.001), and combination immunotherapy, 0.25 (95%CI 0.13-0.48). Additionally, we observe a sexual dimorphism towards males in cardiac adverse reports for arrhythmia, 0.81 (95%CI 0.75-0.87, P &lt;0.001), coronary artery disease, 0.63 (95%CI 0.53- 0.76, P &lt;0.001), myocardial infarction, 0.6 (95%CI 0.53 -0.67, P&lt;0.001), myocarditis, 0.59 (95%CI 0.47- 0.75, P &lt; 0.001) and pericarditis, 0.5 (95% CI 0.35- 0.73, P &lt;0.001).
Conclusion: Our study provides the current risk estimates of cardiac adverse events in patients treated with immunotherapy. Understanding the clinical risk factors that predispose immunotherapy treated cancer patients to fulminant myocarditis is crucial in Cardio-Oncology management.
Citation Format: Jessica A. Castrillon. Cardiovascular adverse events associated with immune checkpoint blockade: analysis of FDA-adverse events database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1698.
Abstract 1699: Direct and indirect immune effects of CMP-001, a virus like particle containing a TLR9 agonist
Authors: Sabree Shakoora , Voigt Andrew , Weiner George J. , Blackwell Sue 
Published: July 2021

Abstract
Background: CMP-001, a virus-like particle (VLP) containing a TLR9 agonist encapsulated by the Qb capsid, is showing promise in early clinical trials when administered intratumorally. Prior work by our group has demonstrated the immunostimulatory effects of CMP-001 are dependent on generation of an anti-Qb antibody response which results in opsonization of CMP-001 by plasmacytoid dendritic cells (pDCs) and production of IFNa. The in vivo efficacy of CMP-001-mediated in situ immunization is T cell dependent. Here, we explore the mechanisms by which the initial effects of CMP-001 on pDCs can activate other cell populations that can contribute to development of an anti-tumor T cell response.
Methods: Uptake of CMP-001 by various cell populations was evaluated by flow cytometry. Gene expression by various immune cell subsets in response to CMP-001 treatment was measured by single cell RNA sequencing (scRNAseq) of normal donor human PBMCs. Additional in vitro experiments were conducted to evaluate direct and secondary effects of CMP-001 on various immune cell subsets.
Results: Anti-Qb antibody-coated CMP-001 were taken up extensively by monocytes with lower levels of uptake by B cells and pDCs. Antibody-coated CMP-001 induced upregulation of interferon-responsive genes and molecules by various cell types including CXCL10, PDL1, and IDO. Much of the impact of CMP-001 plus anti-Qb on monocytes was indirect and mediated by type I interferon. Expression by purified monocytes of PDL1 and IDO was increased in response to IFNa after treatment with CMP-001 plus anti-Qb whereas CXCL10 expression was decreased.
Conclusions: CMP-001 plus anti-Qb induces production of type I interferon by pDCs. Type I interferon has secondary effects on a variety of cell types including monocytes which produce cytokines such as CXCL10 that can potentially impact the development of an anti-tumor T cell response. Uptake of anti-Qb-coated CMP-001 by monocytes has little direct effect on the monocytes. However, uptake of these particles by monocytes does alter the monocyte's response to type I interferon and results in enhanced expression of IDO and PDL1, and suppressed expression of CXCL10, consistent with generation of an immunosuppressive phenotype. These findings shed light on the complexity of the immune response to CMP-001, and provide insight into potential pathways that may be targeted in conjunction with CMP-001 to further enhance the efficacy of this novel approach to immunotherapy.
Citation Format: Shakoora Sabree, Andrew Voigt, George J. Weiner, Sue Blackwell. Direct and indirect immune effects of CMP-001, a virus like particle containing a TLR9 agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1699.
Abstract 170: Anticancer potential of curcuma and target identification in hematologic malignancies: A focus on mismatch repair
Authors: Bhattacharya Priyanjali , Patel Trupti N. 
Published: July 2021

Abstract
Introduction- Cancer, an heterogeneous condition, arises through mutations in the tumor suppressors and proto oncogenes which are otherwise involved in numerous cellular processes.These mutations rewire the signaling cascades to promote ‘malignant phenotype'. Under such circumstances the DNA repair system aids in rectifying the mutations and establishing normalcy.Plant derived products have shown promising success in treatment of cancer. In the present study, we make an attempt to screen various curcumin compounds to identify putative targets related to hematologic malignancies which in turn modulate the functionally altered mismatch repair system (MMR) using computational tools.
Methods-A total of 536 curcumin compounds, retrieved from peer reviewed literature and black turmeric database, were analyzed for molecular characteristics, biological activities, ADME/Tox and, drug-like properties through Molinspiration and PreADMET. This was followed by prediction of site of metabolism via FAME3SOM tool. Simultaneously, COSMIC database was used for selection of proteins associated to haematologic malignancies. The database helped us to identify 9 proteins viz. abl1, max, myb, myc, pcna, p73, top3a, blm and vbp1; molecular aberrations of which are associated with malignant transformation in blood related cancers. Additionally, STRING identified these proteins having significant interaction with proteins of mismatch repair system. The crystal structures of the proteins were obtained from PDB and their domains and active sites were predicted using scanPROSITE, MOTIF Search, metaPOCKET2 and PrankWeb tools. Finally the proteins and ligands were energy minimized using YASARA and subjected to virtual screening and molecular docking using Autodock Vina and Autodock Tools respectively.
Results-The overall results revealed six of the curcuma compounds (two monocarbonyl derivatives, one non-curcuminoid and three black turmeric natural compounds) may have the potential to modulate the identified targets and thus revive the MMR functionality; rescuing the genome from being unstable.
Conclusion-With these analyses we predict that curcumin compounds can modulate therapeutic targets identified here and in turn rescue the function of MMR in hematologic malignancies.
Citation Format: Priyanjali Bhattacharya, Trupti N. Patel. Anticancer potential of curcuma and target identification in hematologic malignancies: A focus on mismatch repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 170.