bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1746: Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma
Authors: Kleiner Ron , Vaskovich Daniella , Pozzi Sabina , Eldar-Boock Anat , Ben-Shushan Dikla , Florindo Helena , Satchi-Fainaro Ronit 
Published: July 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death. Low response rate, acquired resistance, severe side effects, highly desmoplastic and immunosuppressive microenvironment have limited the clinical outcomes of immunotherapy in PDAC. To overcome these hurdles, we set to design a novel immunotherapy that would be safe, efficacious, and selective to PDAC. The failure of immunotherapies to yield clinical response in PDAC is partially attributed to the inefficient antigen presentation by dendritic cells (DC) which results in insufficient T cells stimulation despite their expression of tumor-associated antigens (TAA). DC have an important role in the initiation and regulation of the innate and adaptive arms of the immune system. By efficient presentation of antigens, DC elicit an antigen-specific immune response. Trp53R172H is among the most common TP53 mutations in human PDAC, and is known as one of PDAC TAA. Despite the poor clinical outcomes, longer survival time was observed in PDAC patients with tumors that express high number of TAA combined with an abundant presentation of CD8+ T cell. To that end, we designed a DC-targeted nanoparticle (NP) containing PDAC Trp53R172H TAA and immune potentiators, with the DC targeting moiety, mannose, that was covalently conjugated to the NP, to enhance TAA presentation on DC. This approach led to specific activation of T cells against PDAC's TAA. The therapeutic activity of the NP was evaluated in vitro by our newly established 3D PDAC spheroids model, which is composed of freshly isolated murine stromal cells, therefore, better imitates the complex microenvironment found in PDAC. Along with an in vivo PDAC model, we evaluated the safety profile and therapeutic efficacy of our NP. The NP proposed herein successfully activated splenocytes and induced a specific cytotoxic reaction against PDAC cells ex vivo, which may result in improved survival rate.
Citation Format: Ron Kleiner, Daniella Vaskovich, Sabina Pozzi, Anat Eldar-Boock, Dikla Ben-Shushan, Helena Florindo, Ronit Satchi-Fainaro. Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma [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 1746.
Abstract 1749: DRAK1 suppresses inflammation-induced cervical cancer progression by targeting TRAF6 protein
Authors: Pang Kyoungwha , Lee Jihee , Park Jinah , Ooshima Akira , Yang Kyung-Min , Kim Seong-Jin 
Published: July 2021

Abstract
Cervical cancer is a major cause of mortality in women worldwide and strongly associated with persistent infection with high-risk (HR) human papillomavirus (HPV), mainly HPV16 and HPV18. Most HPV viruses can be cleared by the immune system, and a preventive and effective vaccine against HPV infection decreases the development of cervical cancer. The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) specifically decreases the stability of the TRAF6 protein via an autophagy-mediated degradation pathway by interfering with the homo-oligomerization of TRAF6, eventually suppressing tumor growth and metastasis in inflammation-associated advanced cervical cancer cells. DRAK1 bounds directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL1β signaling-associated pathway and pro-inflammatory cytokine production. DRAK1 knockdown accelerated cervical cancer tumorigenesis and metastasis whereas DRAK1 overexpression suppressed that phenomenon. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel potential biomarker and novel therapeutic target for treatment of TRAF6-associated advanced cervical cancers. [This work was supported by National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (HA17C0037).]
Citation Format: Kyoungwha Pang, Jihee Lee, Jinah Park, Akira Ooshima, Kyung-Min Yang, Seong-Jin Kim. DRAK1 suppresses inflammation-induced cervical cancer progression by targeting TRAF6 protein [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 1749.
Abstract 1750: Human KIT+myeloid cells facilitate visceral organ colonization by melanoma
Authors: Yu Chun I. , Martinek Jan , Wu Te-Chia , Kim Kyung In , George Joshy , Ahmadzadeh Elaheh , Maser Rick , Marches Florentina , Metang Patrick , Authie Pierre , Oliveira Vanessa K. , Wang Victor G. , Chuang Jeffrey H. , Robson Paul , Banchereau Jacques , Palucka Karolina 
Published: July 2021

Abstract
Metastasis is a major risk factor for poor melanoma outcome, but mechanisms supporting distant organ colonization by melanoma are not fully understood. Here, we found that metastatic melanoma tumors from patients are infiltrated by CD33+ myeloid cells. To determine the role of CD33+ cells in melanoma metastasis, we used NSG mice humanized by engraftment of human CD34+ hematopoietic progenitor cells and transgenic expression of human hematopoietic cytokines SCF/GM-CSF/IL-3 (SGM3). Humanized (h)NSG-SGM3 mice enabled development of human CD33+ myeloid cells in the bone marrow and peripheral tissues, and when implanted subcutaneously with human melanoma cell line, supported melanoma colonization of the spleen, liver, lung, and kidneys. Melanoma growth in distant organs was dependent on host SGM3 expression and facilitated by human CD33+ myeloid cells. Deeper characterization attributed this activity to a rare human IL-3- and SCF-dependent CD33+CD11b+CD117+ progenitor cell subset comprising &lt;4% of the total CD45+ leukocyte population. Metastatic tumor-infiltrating CD33+ cells from patients and hNSG-SGM3 mice showed converging transcriptional profiles. Single-cell RNAseq analysis identified a gene signature of a KIT/CD117 expressing CD33+ subset that correlated with decreased overall survival in TCGA melanoma samples. Thus, human CD33+CD11b+CD117+ myeloid cells facilitate metastatic colonization of distant organs by melanoma, representing a novel candidate biomarker as well as a therapeutic opportunity for metastatic melanoma.
Citation Format: Chun I. Yu, Jan Martinek, Te-Chia Wu, Kyung In Kim, Joshy George, Elaheh Ahmadzadeh, Rick Maser, Florentina Marches, Patrick Metang, Pierre Authie, Vanessa K. Oliveira, Victor G. Wang, Jeffrey H. Chuang, Paul Robson, Jacques Banchereau, Karolina Palucka. Human KIT+myeloid cells facilitate visceral organ colonization by 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 1750.
Abstract 1756: The roles of Regnase-1 in pancreatic cancer development and progression
Authors: Okabe Junya , Kodama Takahiro , Takehara Tetsuo 
Published: July 2021

Abstract
Background: Regnase-1 is a RNA-degrading enzyme that plays an important role in the regulation of inflammation by degrading mRNA of inflammation-related genes. Although inflammation is known to promote pancreatic carcinogenesis, involvement of Regnase-1 in this process has never been studied. In this study, we thus investigated the role of Regnase-1 in pancreatic cancer development and progression.
Methods: We examined the expression levels of Regnase-1 in the pancreas of chronic pancreatitis by repeated administration of caerullein in mice. We sought for a regulator of the Regnase-1 expression in Panc-1 pancreatic cancer cell line. We assessed the biological phenotypes caused by siRNA-mediated Regnase-1 inhibition in multiple pancreatic cancer cell lines, including cell proliferation, migration, apoptosis and cytokine expressions. We generated pancreas-specific Kras-activated and Regnase-1-deficient (PDX1-Cre; Kras G12D KI Regnase-1 fl/fl) mice (PKR mice) and examined these phenotypes. We assessed the relationship between the expression levels of Regnase-1 in pancreatic tumor tissue and prognosis in 39 pancreatic cancer patients who underwent curative surgical resection.
Results: The expression levels of Regnase-1 significantly decreased in the murine pancreas of chronic pancreatitis together with the increase in IL-1β. The expression levels of Regnase-1 was downregulated by IL-1β administration in Panc-1 cells. siRNA-mediated Rengase-1 Inhibition significantly promoted cell proliferation, migration and inhibited apoptosis with Bcl-xL upregulation in Panc-1 cells. Rengase-1 Inhibition also upregulated a variety of chemokines involved in the recruitment and activation of myeloid-derived suppressor cells (MDSCs) including CXCL1, CXCL2, CXCL8, CSF2 and CSF3 in Panc1cells. All PKR mice developed pancreatic tumors and became moribund by 3 months of age. We observed massive infiltration of CD11b+Ly6g+Ly6c- PMN-MDSCs and significant upregulation of Arg1, Nos2, Nox2, and S100a8/9 mRNA levels, which are suppressors of anti-tumor immunity known to be secreted from MDSCs. Surgically-resected pancreatic cancer patients with low levels of intra-tumor Regnase-1 expression had significantly shorter recurrence-free and overall survival than those with high levels of Regnase-1. Intratumor Regnase-1 expression levels were negatively correlated with the number of CD11b+ cell infiltration.
Conclusion: Inflammation-mediated downregulation of Regnase-1 may contribute to pancreatic cancer development and progression in cell-autonomous and -heteronomous manners.
Citation Format: Junya Okabe, Takahiro Kodama, Tetsuo Takehara. The roles of Regnase-1 in pancreatic cancer development and progression [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 1756.
Abstract 1757: IFN-γ signaling in myeloid and fibroblastic cells regulates pancreatic cancer growth and metastasis
Authors: Ivleva Elena , Crisostomo Ashley , Andreeva Natalia , Grivennikov Sergei 
Published: July 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents a significant healthcare problem which is on the rise, primarily because of the late stage diagnosis, early metastasis, and rapidly emerging resistance to therapy. As cancer cells in a typical pancreatic tumor are outnumbered by stromal and immune cells, the role of tumor microenvironment in cancer growth and progression is essential. One of the key regulators of tumor microenvironment in numerous cancers is IFN-γ signaling pathway, which is implicated into regulation of multiple cell types. Using a genetic murine model with conditional IFN-γR2 deficiency in myeloid cells, we performed an orthotopic injection of cell line derived from Pdx1Cre-Kras-P53 model (“KPC” cells). The absence of IFN-γ signaling in myeloid cells led to an increase of tumor burden and size of tumors in these mice. Further analysis demonstrated that IFN-γR2 deletion in myeloid cells changes the differentiation of cancer cells in primary tumors, resulting in a loss of characteristic histological pattern and shifting it towards more aggressive phenotype. Subsequent intrasplenic injection/liver spread model revealed that loss of IFN-γR2 in myeloid cells led to increased metastatic outgrowth of PDAC KPC cells. This effect was partially dependent on the gut microbiota. Deficiency of IFN-γR2 in myeloid cells increases recruitment and infiltration of monocytes in normal and tumor liver tissue. Meanwhile, deletion of IFN-γR2 in several subsets of cancer-associated fibroblasts demonstrated that IFN-γ signaling in different subsets of fibroblast/myofibroblasts may play opposing role in PDAC tumor growth. Our data identifies cell type specific IFN-γ signaling pathway as an important regulator of pancreatic cancer progression and metastasis, that can be potentially exploited as a novel immunooncology target or a biomarker of the disease progression.
Citation Format: Elena Ivleva, Ashley Crisostomo, Natalia Andreeva, Sergei Grivennikov. IFN-γ signaling in myeloid and fibroblastic cells regulates pancreatic cancer growth and metastasis [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 1757.
Abstract 1794: Human cancer associated fibroblast subsets can differentially regulate immunotherapy response in head and neck cancer patients
Authors: Graves Diana , Korrer Michael J. , Obradovic Aleksandar Z. , Roy Sohini , Califano Andrea , Drake Charles G. , Kim Young J. 
Published: July 2021

Abstract
The stromal cancer associated fibroblasts (CAF) have been postulated to modulate immune responses, but their role in clinical immunotherapy has not been rigorously explored in detail. To determine potential biomarkers of response and resistance for αPD-1 therapy in head & neck cancer patients, we performed high dimensional immunophenotyping to include single cell RNA sequencing (scRNA-SEQ) from a neoadjuvant trial of 50 advanced-stage head and neck squamous cell carcinoma (HNSCC) patients that were treated with nivolumab. Sufficient suspension cells from the tumors harvested pre and post nivolumab treatment allowed single-cell RNA sequencing on 4 patients as well as bulk RNA sequencing on 40 patients. Using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) and Virtual Inference of Protein-activity by Enriched Regulon (VIPER) bioinformatic analysis platform on the matched scRNA-Seq dataset to capture low expressing genes such as transcription factors, we identified 14 distinct cell types present in HNSCC patients. While CD8 T cells did not show increased number among the responder cohort, T cell cluster analysis showed enhanced IFNγ, granzyme, and perforin. Of these 14 cell types, the CAF cluster showed significant changes among the nivolumab responder cohort. Upon deeper analysis of this fibroblast population, we identified 5 distinct clusters of cancer associated fibroblast subsets (CAF-A, B, C, D, and E) of which, one cluster, CAF-A correlated with patient response to αPD-1 therapy. In order to determine the significance of this CAF subset's function, we isolated CD45-EpCAM-CD31-CD29+FAP+ CAF-A's from primary HNSCC tumor specimens and co-cultured with primary human T cells. Analysis by flow cytometry showed that CAF-A suppresses both CD4+ and CD8+ T cell proliferation as well as activation of these T cells. When we queried the cancer genome atlas, CAF-A gene signature correlated with increased survival, corroborating the important regulatory role of these CAF subsets in the context of endogenous immune responses. Overall, our findings demonstrate the functional importance of CAF subsets in modulating the immunoregulatory milieu of the human HNSCC for the first time, and justifies a more in depth characterization of these stromal cells in human squamous carcinoma in the current era of cancer immunotherapy.
Citation Format: Diana Graves, Michael J. Korrer, Aleksandar Z. Obradovic, Sohini Roy, Andrea Califano, Charles G. Drake, Young J. Kim. Human cancer associated fibroblast subsets can differentially regulate immunotherapy response in head and neck cancer patients [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 1794.
Abstract 1806: Novel preclinical orthotopic and bone metastasis TNBC models for assessment of immunotherapy and chemotherapy responses
Authors: Zdrojewska Justyna , Gladwyn-Ng Ivan , Mäki-Jouppila Jenni H. , Fagerlund Katja M. , Suominen Mari I. , Horn Ross , Rissanen Jukka 
Published: July 2021

Abstract
Triple-negative breast cancer (TNBC) is one of the most complicated types of breast cancer to treat. However, clinical trials continue to demonstrate that combining immunotherapy with chemotherapy can improve survival in patients with metastatic TNBC. In preclinical immunotherapy development, one of the challenges and limitations is the lack of representative TNBC models for advanced metastatic disease that could be used to study survival benefit of these compounds. The aim of this study was to develop local and bone metastatic TNBC models where survival could be followed as primary endpoint, and to assess effects of standard-of-care (Nab-paclitaxel, Abraxane) and anti-PD-1 (pembrolizumab, Keytruda).
Age-matched immunodeficient female CIEA NOG® mice (NOG) and NOG mice engrafted with human CD34+ hematopoietic stem cells (huNOG) were used in the study. In the orthotopic model, the luciferase labelled human TNBC cells, MDA-MB-231(SA)-luc, were inoculated into mammary fat pad of the mice. In the intratibial model, MDA-MB-231(SA)-luc cells were inoculated into bone marrow cavity of tibia to model the growth of primary and bone metastatic TNBC. The treatment with vehicle or paclitaxel (10 mg/kg) in NOG mice or isotype control or pembrolizumab (5 mg/kg) in huNOG mice was started 3 days after cancer cell inoculation and continued twice a week until termination. The mice were sacrificed individually according to predefined sacrifice criteria or latest at study week 8.
Nab-paclitaxel prolonged survival of immunodeficient mice with both primary and metastatic TNBC, but the effect was more profound in the orthotopic model. Pembrolizumab treatment in humanized mice with either tumor site did not result in survival benefit. In an earlier study, we have observed modest tumor growth inhibition with pembrolizumab in the orthotopic model suggesting donor variation effect. The findings are consistent with the clinical studies where pembrolizumab as monotherapy has demonstrated benefit for only some of the TNBC patients. In summary, novel preclinical models mimicking primary and bone metastatic TNBC were established that could be used to study the survival benefit of developing new treatments, including immunotherapies, against local and advanced TNBC.
Citation Format: Justyna Zdrojewska, Ivan Gladwyn-Ng, Jenni H. Mäki-Jouppila, Katja M. Fagerlund, Mari I. Suominen, Ross Horn, Jukka Rissanen. Novel preclinical orthotopic and bone metastasis TNBC models for assessment of immunotherapy and chemotherapy responses [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 1806.
Abstract 1819: The immunosuppressive role of YAP1 on the tumor immune microenvironment
Authors: Zhu Ling-Ling , Liu Jiewei , Chen Jiang 
Published: July 2021

Abstract
Background and aims: Lung adenocarcinoma (LUAD), the most prevalent histologic subtype of non-small cell lung cancer, is one of the most fatal malignancies. Despite the reported direct link between Hippo pathway and suppression of CD8+ and CD4+ T cell function in the context of cancer, its dynamic modulation and tumor microenvironment (TME) in LUAD remain unclear. We aim to investigate the correlation between YAP1 (a major component of Hippo signalling pathway), TME, and the overall survival of patients with LUAD.
Methods: The SsGSEA, CIBERSORT, and ESTIMATE algorithms were applied, and gene set enrichment analysis (GSEA) was conducted to screen Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways between patients with LUAD expressing low and high levels of YAP1 utilizing data downloaded from The Cancer Genome Atlas database. Flow cytometry was performed to detect the immune cell infiltration in LUAD mice model and patients. Western blot and qRT-PCR were used to investigate the mRNA and protein expression of YAP1 from mice model and patients.
Results: In this study, we demonstrated that YAP1 was negatively related to activated CD4/CD8 T cells and positively linked to immature dendritic cell, Tregs, and MDSC in 497 LUAD patients from TCGA, while it was not associated with signatures of 37 immunoregulatory and effector molecules, 37 cytokines. GSEA revealed that the high YAP1 group was not enriched in GO terms and KEGG pathways related to the immune response. However, high level of YAP1 positively correlated to immune score. In LUAD mice model, YAP1 knockout was associated with a reduced Treg cell intratumoural representation, and with higher production of interferon-γ and tumour necrosis factor by CD8+ and CD4+ effector cells (markers of increased cytotoxic activity). Moreover, YAP1 level was negatively related to overall survival in patients.
Conclusion: YAP1 expression within the TME might be useful as a predictive biomarker for immune response and a novel immunotherapeutic prognostic biomarker for LUAD.
Citation Format: Ling-Ling Zhu, Jiewei Liu, Jiang Chen. The immunosuppressive role of YAP1 on the tumor immune microenvironment [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 1819.