bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2785: Efficacy evaluation of candidate therapeutics in immuno-oncology by in vitro suppressive bioassays using macrophages
Authors: Janss Thibaut J. , Arnold Joahn , Lamy Juliette , Boelen Ellen 
Published: July 2021

Abstract
The increasing interest in the tumor microenvironment leads to a focus on new bioassays to represent all the players of the cancer immune response. Some of these players like Tumor Associated Macrophages (TAMs) often exhibit an immunosuppressive phenotype by downregulating the anti-tumor response. Their regulation mechanisms constitute an important target for new therapeutics. In order to study these mechanisms in a human model, suppressive bioassays mimicking the suppressive action of these cells on T cell activation, were developed. An important player in the tumor microenvironment are macrophages which possess important active and regulatory functions in both innate and adaptive immune responses. Classical activated macrophages, classified as M1-like macrophages, comprise immune effector cells with an acute inflammatory phenotype while the alternatively activated M2-like macrophages have suppressive and healing capacities. TAMs are present at high densities in solid tumors and share many characteristics with M2-like macrophages. In vitro assays using M1- and M2-like macrophages can be a first step to screen the effect of the test molecules on the phenotype and function of macrophages. For example, macrophage precursors display extraordinary plasticity in response to exogenous and endogenous stimuli which can result in a M2- or M1-like status. Using in vitro polarization and functional assays, the potential effect of molecules on M1- and M2-like macrophage generation and polarization can be screened. Next to that, the test molecules' impact on the functionality of macrophages can be evaluated in a suppressive assay. Here, the ability of the molecules to reverse the stimulating versus suppressive effect of the M1- and M2-like macrophages on T cells can be determined by measuring proliferation and cytokine production. The use of bioassays contributes to a better understanding of the tumor microenvironment. The steps needed to generate an anti-tumor response by the immune system will help to assess the functional potential of new drugs, design clinical trials and ultimately discover relevant biomarkers
Citation Format: Thibaut J. Janss, Joahn Arnold, Juliette Lamy, Ellen Boelen. Efficacy evaluation of candidate therapeutics in immuno-oncology by in vitro suppressive bioassays using macrophages [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 2785.
Abstract 2786: A FcgR IIB tumor enriching anti-CD137 novel antibody to avoid liver Immuno-toxicity
Authors: Xue Jie , Chang Jen-Kuan , Dong Chen , Mao Yi-Ting , Raghavendra Pallavi , Li Ou , Issafras Hassan , Xu Wenfeng , Jiang Weidong 
Published: July 2021

Abstract
CD137 (4-1BB/TNFRSF9) is a costimulatory T-cell receptor belonging to the TNF receptor superfamily which is transiently expressed on T cell and NK cells. Targeting CD137 or its natural ligand 4-1BB ligand (4-1BBL) has important implications in many clinical conditions, including cancer. Anti-CD137 agonistic anti-CD137 antibodies have shown potent, often curative anti-tumor activity in preclinical models. In depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes and high amounts of cytokines, including IFN-γ. However, this approach has suffered significant setback in the clinic due to either dose-dependent severe liver toxicity (e.g. Urelumab), or lack of single agent activity in the case of Utomilumab. Multiple therapeutics that attempt to restrict 4-1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. Here we present a novel antibody targeting 4-1BB receptor, named HLX25 with engineered Fc region to enhance the binding to FcγR IIB. In vitro, HLX25 induces comparable or superior CD137 activation and IL-2 release compared to Urelumab and Utomilumab, suggesting potentially a better safety profile. We showed that HLX25 binds to unique non-ligand competing epitope, which is different from both Urelumab and Utomilumab. In vivo, HLX25 shows potent dose-dependent single agent anti-tumor activity as low as 0.3mg/kg in MC38 model without sign of liver toxicity up to 20 mg/kg, suggesting superior efficacy and better safety profile.
Citation Format: Jie Xue, Jen-Kuan Chang, Chen Dong, Yi-Ting Mao, Pallavi Raghavendra, Ou Li, Hassan Issafras, Wenfeng Xu, Weidong Jiang. A FcgR IIB tumor enriching anti-CD137 novel antibody to avoid liver Immuno-toxicity [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 2786.
Abstract 2788: Deep characterization of tumor infiltrating leukocytes using a combination of flow cytometry and single-cell multiomics
Authors: Shi Xiaoshan , Nakamoto Margaret , Middlebrook Aaron , Huang Wei , Lo Evelyn , Neuhoefer Patrick T. , Bornheimer Scott , Ghanekar Smita 
Published: July 2021

Abstract
Cancer immunotherapies have the potential to induce durable anti-tumor immune responses; however the efficacy of these treatments varies among patients and partially depends on the complex interplay between malignant cells and non-malignant cells within the tumor microenvironment. In the tumor microenvironment, T cells play a crucial role in eliminating tumor cells and orchestrating anti-tumor immune responses; in contrast immunosuppressive cell types such as myeloid-derived suppressor cells can support tumor progression. Here we harnessed recent advances in single-cell multiomics that allow high-resolution functional characterization of intratumoral immune cells to improve our understanding of their dynamic relationships. Specifically, we utilized a One Solution Workflow to dissociate a solid tumor followed by in-depth dissection of the immune composition of the tumor microenvironment using both flow cytometry and the BD Rhapsody™ Single-Cell Analysis System. We characterized the cellular composition of tumor microenvironment using flow cytometry analysis. Importantly, by examining the expression of mRNA and surface protein markers at single-cell resolution, we unraveled the complexities of the tumor microenvironment, elucidated cellular heterogeneity and identified cell-type specific gene signatures. We propose this One Solution Workflow can be adopted to understand the transcriptional and proteomic phenotypes of tumor infiltrating leukocytes for development of novel immune therapeutic strategies for cancer.
For Research Use Only. Not for use in diagnostic or therapeutic procedures. Class 1 Laser Product.BD-23279 (v1.0) 1120BD, the BD Logo and Rhapsody are trademarks of Becton, Dickinson and Company or its affiliates. © 2020 BD. All rights reserved.
Citation Format: Xiaoshan Shi, Margaret Nakamoto, Aaron Middlebrook, Wei Huang, Evelyn Lo, Patrick T. Neuhoefer, Scott Bornheimer, Smita Ghanekar. Deep characterization of tumor infiltrating leukocytes using a combination of flow cytometry and single-cell multiomics [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 2788.
Abstract 2794: Blocking histamine receptor H1 on macrophages with anti-allergy drugs restores T-cell anti-tumor immunity
Authors: Li Hongzhong , Xiao Yi , Yao Jun , Yuan Xiangliang , Yin Xuedong , Zhang Yuan , Saito Yohei , Yagita Hideo , Gibbons Don , Yu Dihua 
Published: July 2021

Abstract
CD8+ T lymphocytes in tumors often become dysfunctional, prompting cancer immune escape and immunotherapy resistance. Restoring T-cell anti-tumor immunity remains an unmet challenge. Here, we show that histamine receptor H1 (HRH1) is highly expressed and tightly associated with T-cell dysfunction in human cancers. Histamine, the HRH1 ligand, is also increased in human and mouse tumors. HRH1 is predominantly expressed on tumor-associated macrophages (TAMs) and is activated by cancer cell-secreted histamine. The histamine/HRH1 axis in TAMs confers CD8+ T-cell dysfunction via increasing membrane localization of V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint that promotes immunotherapy resistance. Blocking HRH1, genetically, or by anti-allergy drugs, reversed immunosuppressive TAMs, activated T-cells, and inhibited tumor growth in vivo. HRH1-targeting anti-allergy drugs more efficaciously enhanced immunotherapy response than anti-VISTA antibodies. Markedly, allergy-induced histamine also activates HRH1 on macrophages to induce T-cell dysfunction and immunotherapy resistance, which were reversed by the over-the-counter anti-allergy drug. Taken together, tumor cell-derived and allergy-released histamines activate HRH1 on TAMs to concede immunosuppression, pro-tumor function, and immunotherapy resistance, which can be negated by inexpensive and safer anti-allergy drugs.
Citation Format: Hongzhong Li, Yi Xiao, Jun Yao, Xiangliang Yuan, Xuedong Yin, Yuan Zhang, Yohei Saito, Hideo Yagita, Don Gibbons, Dihua Yu. Blocking histamine receptor H1 on macrophages with anti-allergy drugs restores T-cell anti-tumor immunity [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 2794.
Abstract 280: Sub-30-nm capsules for drug delivery
Authors: Ma Xiaowei , Zhang Ping , Cui Chao , Ling Chang-Chun , Cui Lina 
Published: July 2021

Abstract
Systemic treatment of cancer using long-circulating nanomedicines is promising due to their passive tumor targeting ability to achieve higher and more selective accumulation in tumors with irregular vascularization, a phenomenon known as extended permeation and retention (EPR) effect.1,2 Clinical use of nanometer-sized carriers, such as Doxil and Abraxane, to deliver chemotherapeutics to solid tumors is proven effective in highly vascularized tumors such as breast cancer, ovarian cancer, multiple myeloma, and Kaposi's sarcoma.3-5 Most nanomedicines that are being developed or approved so far have a diameter of around 100-200 nm for prolonged retention in highly angiogenic and densely vascularized tumors,6 however, they suffer from limited accumulation and poor penetration to the inner core of avascular or hypovascular tumors (such as prostate and pancreatic cancer),7-9 therefore nanomedicines small than 100 nm are more preferred for improved tumor penetration.10,11 Here we present our strategy to form cyclodextrin-based sub-30-nm nanocarriers, which allows easy drug encapsulation, and successful delivery of therapeutics to human tumor xenografts with significantly reduced tumor growth rates and improved survival rates.
Citation Format: Xiaowei Ma, Ping Zhang, Chao Cui, Chang-Chun Ling, Lina Cui. Sub-30-nm capsules for drug delivery [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 280.
Abstract 2824: SHP2-PDHA metabolic axis is critical for adipocyte function by mitigating ER stress-induced adipocytes dysfunction: Implication for obesity-driven pancreatic ductal adenocarcinoma progression
Authors: Olou Appolinaire A. , Jack Jarrid , Manley Sharon , Ambrose Joseph , Walsh McKinnon , Eades Austin , VanSaun Michael N. 
Published: July 2021

Abstract
Obesity remains a major risk factor for the development of pancreatic cancer. Animal studies demonstrated that obese mice develop larger and more metastatic pancreatic cancer compared to their lean counterpart. Within the tumor environment are adipocytes that secrete adipokines, which promote inflammation and directly stimulate pancreatic cancer cells. Understanding the mechanisms that alter adipocyte function and adipokine secretion is critical for circumventing adipocyte-mediated influence on pancreatic cancer progression. Targeting of the Src homology region 2 containing protein tyrosine phosphatase (SHP-2) in the cancer cells has recently shown promising potential, yet the effect of SHP2 inhibition on stromal components has not been addressed. Here we demonstrate that SHP2 and the mitochondrial protein pyruvate dehydrogenase (PDHA) are critical mediators of adipocyte function, through mitigation of ER stress in adipocytes. In order to understand the role of SHP2 and PDHA in adipocytes, we performed Oil Red O staining and western blot assays on cultured adipocytes. We found that the transition from pre-adipocytes to fully developed adipocytes is marked by significant accumulation of phospho-SHP2, PDHA and the ER stress marker Bip. Chemical inhibition of SHP2 or PDHA augmented ER stress and impaired lipid production in the adipocytes; these effects were reversed by the ER stress inhibitor, 4-Phenylbyturic acid (4-PBA). Moreover, pancreatic cancer cells exposed to conditioned media from differentiated adipocytes, in which either SHP2 or PDHA was inhibited, are less aggressive and invasive compared to PDAC cells grown in conditioned media from control adipocytes with no inhibitor treatment. Therefore, our studies indicate that SHP2 and PDHA, in adipocytes, are key mediators of obesity-driven pancreatic cancer progression. Future studies will focus on understanding the SHP2-PDHA axis in adipocytes and further to elucidate how cancer cell extrinsic effects of SHP2 inhibition could alter PDAC progression.
Citation Format: Appolinaire A. Olou, Jarrid Jack, Sharon Manley, Joseph Ambrose, McKinnon Walsh, Austin Eades, Michael N. VanSaun. SHP2-PDHA metabolic axis is critical for adipocyte function by mitigating ER stress-induced adipocytes dysfunction: Implication for obesity-driven pancreatic ductal adenocarcinoma 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 2824.
Abstract 2825: Mechanosurveillance by immunity targets mechanical compliance of metastatic cells
Authors: Tello-Lafoz Maria , Srpan Katja , Hu Jing , Romin Yevgeniy , Calo Annalisa , Hsu Katharine C. , Massagué Joan , Huse Morgan , Er Ekrem Emrah 
Published: July 2021

Abstract
Metastatic dissemination of cancer cells to vital secondary organs pose a lifelong lethal threat unless they can successfully be eliminated by the immune system. Interestingly, despite their ability to evade immunity at primary organs, the vast majority of disseminated cancer cells are killed at secondary organs, suggesting that the process of dissemination renders cancer cells sensitive to immunity. Understanding how dissemination renders cancer cells sensitive to immunity would therefore provide exciting new opportunities to target metastases, but the relationship between dissemination and the immune response is not clear. In our effort to study this relationship, we manipulated cancer cells' expression of myocardin related transcription factors A and B (MRTFA/B), which are central in regulation of actin cytoskeleton and are indispensable for metastatic invasion, dissemination and colonization. Surprisingly, despite MRTFA/B's established roles in promoting metastasis, we found that MRTFA/B expression in cancer cells downregulated metastatic colonization in fully immuno-competent mouse models. MRTFA/B mediated decrease in colonization was completely reversed upon immune cell depletion suggesting that the immune cells exploit MRTFA/B expression in cancer cells for cytotoxicity. Among various cancer cell parameters involved in immune cell activation, T- and NK cell activation most prominently correlated with MRTFA/B driven mechanical compliance of cancer cells. Mechanical compliance, also known as stiffness, of antigen presenting cells and synthetic substrates are well-known to activate T- and NK cells through biophysical and mechano-chemical signal transduction. As such, perturbing cancer cells' stiffness downregulated the immune response and cytotoxicity. Thus, we termed this process mechanosurveillance. Our work on mechanosurveillance will help us understand how disseminated cancer cells are targeted by immunity and how they evade it at secondary organs. Importantly the concept of mechanosurveillance will help guide the use of existing therapeutics that alter tissue stiffness and immune boosting therapies to combat metastases.
Citation Format: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calo, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er. Mechanosurveillance by immunity targets mechanical compliance of metastatic cells [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 2825.
Abstract 2832: Targeted genomic landscape of metastases compared to primary tumors in non-small-cell lung cancer
Authors: Chen Bing , Dong Gaochao , Liang Yingkuan , Zhang Te , Zhang Junling , Chen Shiqing , Jiang Feng , Xu Lin 
Published: July 2021

Abstract
The genomic landscape of primary non-small-cell lung cancer (NSCLC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in NSCLC metastases, and how it compares with primary tumors in general. The genomic landscape of metastases may be important for clinical treatment and prognosis. In this retrospective study, 37 cases of surgically resected NSCLC were studied, of which 19 were non-metastatic NSCLC and 18 were metastatic NSCLC. Sixty formalin-fixed paraffin-embedded (FFPE) tissue samples from 37 NSCLC patients, including the primary lesion of non-metastatic NSCLC (Group A, N =19), the primary lesion of metastatic NSCLC (Group B, N =18), and lymph node lesions (Group C, N =23), were included to detect somatic mutations using a 1021-gene panel by next-generation sequencing (NGS). In this study, twenty-nine patients (78.4%) were male. Nineteen patients with lung adenocarcinoma (LUAD) and 18 with lung squamous cell carcinoma (LUSC) were included. In addition, there were significant differences between Groups A and B in stage T and stage N (P &lt; 0.0001). Overall, EGFR (33.3% vs 15.8%) and TERT (16.7% vs 5.2%) were numerically more frequently mutated in metastases, but differences were not statistically significant. Moreover, we found that ARID1A may be closely related to metastasis in LUSC (P = 0.029). These data support the theory that primary and metastatic NSCLC encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. While ARID1A may be closely related to metastasis in LUSC.
Citation Format: Bing Chen, Gaochao Dong, Yingkuan Liang, Te Zhang, Junling Zhang, Shiqing Chen, Feng Jiang, Lin Xu. Targeted genomic landscape of metastases compared to primary tumors in non-small-cell lung cancer [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 2832.
Abstract 2842: 6-gingerol attenuates metastasis in aged mice model of colorectal cancer through modulation of epithelial-mesenchymal transition mediators genes and e-cadherin upregulation
Authors: Ajayi Babajide Oluwaseun , Adenigba Ayomiposi , Adeshina Anuoluwapo 
Published: July 2021

Abstract
Colorectal cancer (CRC) is the third most common cancer in America, and the third cause of cancer related death. Metastasis is the major cause of death in patient with CRC. Many CRC are likely to spread from primary site to the other parts of the body before and after detection of malignant tumor. 6-gingerol, the bioactive component of fresh ginger have been reported to have myriad of biological activities including anti-inflammatory and antioxidant properties. We have previously reported the anti-CRC effect of 6-gingerol. However there is dearth of information on the anti-metastatic effect 6-gingerol in CRC. Thus, the effect of 6-gingerol on epithelial-mesenchymal transition mediators' genes and E-Cadherin repression in aged mice model of CRC was assessed in this study. Following institutional ethical approval. Aged male BALB/c mice (10 months) were divided into four groups of 10 mice each. Mice were fed with AIN-93 diet and allowed access to water ad libitum. Group 1 mice serve as control, group 2 mice received 6-gingerol 10mg/kg/day by oral gavage for 10 weeks. Group 3 mice received a single dose of azoxymethane (AOM) 10mg/kg (iP) and on the seventh day they received three cycles of dextran sulfate sodium (DSS) 2% (W/V) in drinking water ( each cycle is define as one week of DSS followed by two weeks of plain drinking water) Group 4 mice received 6-gingerol 10mg/kg/day by oral gavage in combination with single dose of azoxymethane 10mg/kg (iP) and on the seventh day they received three cycles of dextran sulfate sodium salt 2% (W/V) in drinking water. Mice were humanely sacrificed under anesthesia and colon tissues were processed for RT-PCR and multiplex immunohistochemistry analysis. Mice that received both 6-gingerol and AOM and DSS showed a significant decreased expression of Lymphocyte function-associated antigen-1, N-cadherin, SNAIL 1, ZEB 1, AP4 and HMGA1 with concomitant Upregulation miR-34, miR-15a, miR-218 and miR-302 expression as compared with the AOM and DSS only group. The result obtained from this study showed 6-gingerol inhibited metastasis through modulation of epithelial-mesenchymal transition mediators' genes and E-Cadherin upregulation, and as such 6-gingerol could be a promising anti-metastatic agent in CRC treatment.
Citation Format: Babajide Oluwaseun Ajayi, Ayomiposi Adenigba, Anuoluwapo Adeshina. 6-gingerol attenuates metastasis in aged mice model of colorectal cancer through modulation of epithelial-mesenchymal transition mediators genes and e-cadherin upregulation [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 2842.