bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A73: Human granulocytic myeloid-derived suppressor cells (G-MDSCs) in metastatic breast cancer patients is a heterogeneous population with angiogenic potential in vivo
Authors: Mehmeti Meliha , Bergenfelz Caroline , Bexell Daniel , Carlsson Robert , Hellsten Rebecka , Larsson Anna-Maria , Loman Niklas , Riesbeck Kristian , Ahl Jonas , Rydberg-Millrud Camilla , Paul-Visse Gesine , Rydén Lisa , Killander Fredrika , Leandersson Karin 
Published: June 2021

Abstract
MDSCs are potent immunosuppressive myeloid cells that have been implicated in various diseases, including cancer. In humans, MDSCs are divided into Mo-GMDSCs and G-MDSCs subgroups, depending on their surface phenotype and function. While their immunosuppressive properties have been extensively studied, knowledge about their origin and their tumor-promoting functions per se remains scarce. In this study, we demonstrate that G-MDSCs are significantly enriched in the peripheral blood of locoregional recurrent metastatic breast cancer (LRR/MBC) compared to healthy donors. The G-MDSCs display a heterogeneous population with a morphology representing one blast-like and one polymorphonuclear (PMN) population. In a breast cancer xenograft model, co-transplanting G-MDSCs sorted from LRR/MBC together with breast cancer cells significantly promoted angiogenesis and tumor growth. Gene expression profiling analysis revealed that G-MDSCs from LRR/MBC rather clustered with neutrophils from healthy donors, sharing similar expression in genes relevant for angiogenesis, lymphangiogenesis and immunosuppression, but surprisingly not with G-MDSCs from sepsis patients. We conclude that enrichment of G-MDSCs in metastatic breast cancer represents a heterogeneous population of activated neutrophils that can promote angiogenesis and tumor progression, and immature blasts of yet unknown character.
Citation Format: Meliha Mehmeti, Caroline Bergenfelz, Daniel Bexell, Robert Carlsson, Rebecka Hellsten, Anna-Maria Larsson, Niklas Loman, Kristian Riesbeck, Jonas Ahl, Camilla Rydberg-Millrud, Gesine Paul-Visse, Lisa Rydén, Fredrika Killander, Karin Leandersson. Human granulocytic myeloid-derived suppressor cells (G-MDSCs) in metastatic breast cancer patients is a heterogeneous population with angiogenic potential in vivo [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A73.
Abstract A74: Cytomegalovirus infection of melanoma delays tumor growth by recruiting and altering monocytic phagocytes in the tumor
Authors: Wilski Nicole A. , Del Casale Christina , Alexeev Vitali , Daskalakis Constantine , Purwin Timothy J. , Aplin Andrew E. , Snyder Christopher M. 
Published: June 2021

Abstract
Herpesvirus-based immunotherapies are emerging as exciting new possibilities for vaccines and cancer treatment. We have been exploring the use of a cytomegalovirus (CMV)-based cancer therapy to promote productive tumor-specific immunity and modify the tumor microenvironment. We previously showed that intratumoral (IT) infections with murine (M)CMV led to significant delays in the growth of B16 melanomas that were, surprisingly, independent of vaccine antigens encoded in the viral backbone. Although MCMV could infect B16 cells directly in vitro, tumor-associated macrophages (TAMs) were a primary target for viral infection in vivo. To test the mechanistic role of TAMs, we depleted monocytic phagocytes with clodronate. Loss of these myeloid cells completely prevented MCMV from delaying tumor growth. Macrophages are well-known targets of MCMV infection and in vitro studies demonstrated that MCMV infection of M2-polarized macrophages resulted in repolarization to an M1-like phenotype. In vivo, MCMV infection also increased expression of several inflammatory cytokines in the tumor. In a natural infection, MCMV uses the chemokine MCK-2 to recruit monocytes to the site of infection. Strikingly, MCMV deficient in MCK-2 was ineffective at delaying tumor growth. Further studies demonstrated that MCK-2 was necessary for MCMV to induce macrophage accumulation in the tumor and infiltration into the center of lesions. Finally, we found that repeated IT injections of MCMV caused more marked tumor growth delay and resulted in increased tumor clearance. Together, our results show that MCMV promotes tumor growth delay by modulation of the TAM compartment through recruitment of new macrophages via viral MCK-2 and infection of TAMs to promote an M1-like state within the tumor.
Citation Format: Nicole A. Wilski, Christina Del Casale, Vitali Alexeev, Constantine Daskalakis, Timothy J. Purwin, Andrew E. Aplin, Christopher M. Snyder. Cytomegalovirus infection of melanoma delays tumor growth by recruiting and altering monocytic phagocytes in the tumor [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A74.
Abstract A76: Anti IL-1b as a cancer immunotherapy
Authors: Singh Reshma , Diwanji Rohan , Jayaraman Pushpa , Chiang Derek , Sabatos-Peyton Catherine , Dranoff Glenn 
Published: June 2021

Abstract
Inflammation in cancer can both suppress tumor growth and promote tumorigenesis. In the tumor microenvironment (TME), inflammation characterized by inflammatory cells and other mediators including cytokines affects tumor development and progression and can have an impact on response to therapy. The inflammatory cytokine IL-1b is upregulated in several conditions including rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease, as well as in different cancers including breast, gastric, pancreatic, and lung cancers. IL-1b contributes to the generation and accumulation of myeloid-derived suppressor cells (MDSCs). In the tumor microenvironment, MDSCs consist of a mixture of immature macrophages, immature dendritic cells and neutrophils, which can suppress the function of antitumor T cells. In addition, IL-1b is produced via activation of the inflammasome, which has been shown to promote the infiltration of MDSCs and tumor-associated macrophages (TAMs) into the TME. Downstream of IL-1b production are other inflammatory cytokines such as IL-6, IL-8, and IL-17, which can also suppress the immune system. Recently published data show that blocking IL-1b in patients without cancer can lead to a decrease in fatal cancer and more specifically lung cancer incidences and fatalities (Ridker et al., 2017). While the study was not designed to study the anticancer effects of canakinumab (Ilaris), this finding has led to increased interest in understanding the role of IL-1b and IL-1b blockade in cancer development and progression. Emerging data aim to elucidate the role of IL-1b blockade on tumor growth and progression, as well as characterize changes to tumor-infiltrating lymphocyte (TIL) populations and their function after treatment with an anti-IL-1b antibody.
Reference: Ridker PM et al. Effect of interleukin-1b inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomized, double-blind, placebo-controlled trial. Lancet 2017;390:1833-42.
Citation Format: Reshma Singh, Rohan Diwanji, Pushpa Jayaraman, Derek Chiang, Catherine Sabatos-Peyton, Glenn Dranoff. Anti IL-1b as a cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A76.
Abstract B16: Enabling checkpoint inhibitors with oncolytic viruses to deliver complete responses: A matter of timing
Authors: Cervera-Carrascon Victor , Quixabeira Dafne , Munaro Eleonora , Santos Joao M. , Havunen Riikka , Siurala Mikko , Hemminki Akseli 
Published: June 2021

Abstract
Checkpoint inhibitors (CPI) started a new golden era of immunotherapy for cancer treatment. Since approval of the first product in 2011, a number of these antibodies are now available for different indications. Hundreds of trials are ongoing, which could predict many further approvals soon. Unfortunately, only a minority of patients currently benefit from CPI treatment. One of the biggest limitations appears to be poor immune infiltration of many tumors, known as immune desert or excluded tumors. Oncolytic viruses are an interesting tool to use together with CPI to increase the frequency and the quality of patients’ responses. Besides their inherent ability to raise the immune alarm towards the tumor, resulting in recruitment of lymphocytes and other cells, they can be armed with transgenes to potentiate these effects. In a data-driven approach, adenoviruses expressing Tumor Necrosis Factor Alpha and Interleukin 2 were identified as the optimal approach for recruiting and activating T cells in tumors. In this approach, the regimen of administration must be considered as it can affect the outcome of the treatment. We used an aggressive and immunosuppressive solid tumor model (B16.OVA melanoma) to study the interaction between the above-mentioned viruses and anti-PD-1 and anti-PD-L1. After optimizing treatment regimes, control of every tumor led to complete responses in 100% of the animals when the viral platform and anti-PD-1 (or anti-PD-L1) were used together. This was a significant improvement when compared to them used as monotherapies (p-value &lt;0.01), but the optimal regimens of administration were different for anti-PD-1 and for anti-PD-L1. Full data, including tumor growth control, survival and extensive immunologic characterization, revealing the mechanism of action, will be presented. Checkpoint inhibitors and oncolytic adenovirus are an attractive approach for increasing the proportion of patients benefiting from CPI therapy. It is of critical relevance to understand how to best use them to maximize their therapeutic effect. Our study underlines the importance of scheduling of the agents with each other, and the differences between CPI targets.
Citation Format: Victor Cervera-Carrascon, Dafne Quixabeira, Eleonora Munaro, Joao M. Santos, Riikka Havunen, Mikko Siurala, Akseli Hemminki. Enabling checkpoint inhibitors with oncolytic viruses to deliver complete responses: A matter of timing [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B16.
Abstract B38: Hypoxia mediates downregulation of mTOR via miR-100 in cervical cancer cells
Authors: Takamizawa Shigeatsu , Yamanaka Zenta , Nishi Hirotaka 
Published: June 2021

Abstract
Objectives: Hypoxia occurs during development of cervical cancer and is considered to correlate with its malignancy. We found that hypoxia induced miR-100 whose expression was low in cervical cancer. We sought to determine the target molecules during hypoxia in cervical cancer.
Methods and Results: We found that the expression of miR-100 was significantly higher under hypoxic condition (1% O2) by realtime RT-PCR. According to the results of in silico analysis, miR-100 targeted mechanistic target of rapamycin (mTOR). Hypoxia and overexpression of miR-100 respectively decreased the activity of luciferase-reporter containing the 3’-untranslated region (UTR) of mTOR with the predicted miR-100-binding site in cervical cancer cell lines, CA and HeLa. By Western blot analysis, hypoxia downregulated the endogenous mTOR protein expression. mTOR mRNA level was also downregulated by hypoxia using realtime RT-PCR.
Conclusions: Our results suggest that miR-100 and mTOR could be a therapeutic target for cervical cancer.
Citation Format: Shigeatsu Takamizawa, Zenta Yamanaka, Hirotaka Nishi. Hypoxia mediates downregulation of mTOR via miR-100 in cervical cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B38.
Abstract B74: Immunologic characteristics of circulating tumor cells in patients with head and neck squamous cell carcinoma
Authors: Tada Hiroe , Takahashi Hideyuki , Ishii Hiroki , Kuwabara-Yokobori Yuki , Ida Shota , Shino Masato , Chikamatsu Kazuaki 
Published: June 2021

Abstract
Circulating tumor cells (CTCs) are cells that have shed from the tumor tissue into the bloodstream, and detection and enumeration of CTCs have been recognized as a useful test for personalized cancer therapy. Moreover, characterization of CTCs including epithelial-mesenchymal transition, stemness, and immune evasion phenotype is essential for a deeper understanding of cancer biology. To assess the immunologic characteristics of CTCs, we investigated the expression profile of immune-regulatory molecules, PD-L1, PD-L2, and CD47 in CTCs derived from patients with head and neck squamous cell carcinoma (HNSCC). Furthermore, the PD-L1 expression in the CTCs was compared with that in the tumor tissues assessed by immunohistochemistry. CTCs were isolated from 26 HNSCC patients with recurrent and/or distant metastasis by depletion of CD45-positive cells, and the expression of four epithelial markers (EpCAM, CK-19, EGFR, and c-Met) was first analyzed by qRT-PCR with a low concentration of RNA from the CTC population. Twenty (76.9%) of 26 patients tested were positive for at least one epithelial-related gene, indicating the existence of CTCs in those patients. Among 20 CTC-positive patients, 16 (80%), 13 (65%), and 15 (75%) patients were positive for CD47, PD-L1, and PD-L2, respectively. Of note, the mRNA expression level of each immune-regulatory molecule correlated positively with each other (PD-L1 vs PD-L2, p = 0.0028; PD-L1 vs CD47, p = 0.0015; PD-L2 vs CD47, p &lt; 0.0001). Although the PD-L1 expression in the tumor tissues was positive in 12 (60%) of the 20 patients, concordance of the PD-L1 expression between the tumor tissues and the CTCs was observed in only 11 (55%) patients. Our findings suggest that, in some patients, CTCs may facilitate their evasion of innate and acquired antitumor immunity mediated via effector T cells, NK cells, and macrophages by expressing multiple immune-regulatory molecules. Currently, precise evaluation of PD-L1 expression are indispensable for the development of more effective and personalized therapeutic approaches using immune checkpoint inhibitors; therefore, the evaluation of PD-L1 expression in CTCs may enable real-time assessment as well as continuous monitoring of the PD-L1 status in tumor cells within tumor microenvironment.
Citation Format: Hiroe Tada, Hideyuki Takahashi, Hiroki Ishii, Yuki Kuwabara-Yokobori, Shota Ida, Masato Shino, Kazuaki Chikamatsu. Immunologic characteristics of circulating tumor cells in patients with head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B74.
Abstract B76: Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients
Authors: Truxova Iva , Kasikova Lenka , Hensler Michal , Skapa Petr , Laco Jan , Pecen Ladislav , Belicova Lucie , Praznovec Ivan , Halaska Michael J. , Brtnicky Tomas , Salkova Eva , Rob Lukas , Kodet Roman , Goc Jeremy , Sautes-Fridman Catherine , Fridman Wolf Herman , Ryska Ales , Galluzzi Lorenzo , Spisek Radek , Fucikova Jitka 
Published: June 2021

Abstract
A high density of tumor-infiltrating CD8+ T cells and CD20+ B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP+ DCs is robustly associated with an immune contexture characterized by TH1 polarization and cytotoxic activity. We showed that both mature DCs and CD20+ B cells play a critical role in the generation of a clinically favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naive HGSC patients. Our findings suggest that the presence of mature, DC-LAMP+ DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically relevant anticancer immunity.
Citation Format: Iva Truxova, Lenka Kasikova, Michal Hensler, Petr Skapa, Jan Laco, Ladislav Pecen, Lucie Belicova, Ivan Praznovec, Michael J. Halaska, Tomas Brtnicky, Eva Salkova, Lukas Rob, Roman Kodet, Jeremy Goc, Catherine Sautes-Fridman, Wolf Herman Fridman, Ales Ryska, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B76.
Abstract B91: Plasmacytoid dendritic cells in HPV+ and HPV- head and neck cancer
Authors: Koucký Vladimír , Hladíková Kamila , Bouček Jan , Fialová Anna 
Published: June 2021

Abstract
Introduction: Plasmacytoid dendritic cells (pDC) are the most important IFN type I producing cells. They play an essential role in viral infections; however, they are studied in context of many pathologic conditions including malignancies. Data show their negative effect on patient prognosis in breast, ovarian, skin and oral cancer, but also a possible antitumoral effect is discussed. In case of head and neck cancer (HNSCC), it is assumed that tumor-infiltrating pDC (TIpDC) are dysfunctional and support immunosuppressive environment. Hence, there are no data on the functional state of pDC in relation to HPV status of tumors, despite the fact that a dominant part of oropharyngeal cancer is viral-driven, having better prognosis.
Methods: Phenotype and functional state of pDC in tumor-derived single-cell suspensions, tonsils and PBMC was analyzed by flow cytometry. Plasmacytoid DC were identified as CD45+, Lineage -, CD4+, BDCA2+, CD123+ cells. Expression of stimulatory and regulatory molecules (TLR7, TLR 9, NKp44, TIM3, IDO, Granzyme B) was assessed. Cytokine levels in cell culture supernatants were detected using Luminex (IFNα, IFNγ, IL-10, IL-12, IL-17, IL-3, IL-4, IL-6, TNFα, TNFβ). For stimulatory tests CpG A 2216 and Imiquimod were used.
Results: We found higher proportions of circulating pDC in HPV+ patients (p=0.045). However, there was no difference in numbers of TIpDC in HPV+ and HPV- HNSSC. We also observed the same number of TIpDC able to react to TLR 7 and TLR 9 stimulation. Nevertheless, pDC from HPV+ tumors showed a potential to produce significantly higher levels of IFNα upon CpG A stimulation (p=0.013). In relation to this, surprisingly, NKp44 expression, referred as negative regulator of IFNα secretion in tonsils, was higher in HPV+ patients (p=0.049). There was no correlation with other regulatory molecules expressed on pDC nor the number of tumor-infiltrating Tregs.
Conclusion: Plasmacytoid DC might play an important role in regulation of tumor microenvironment in patients with HNSCC. Our data show functional differences between pDC infiltrating HPV+ and HPV- cancer, suggesting that these cells contribute to the different biology and prognosis of HPV-induced cancer.
Citation Format: Vladimír Koucký, Kamila Hladíková, Jan Bouček, Anna Fialová. Plasmacytoid dendritic cells in HPV+ and HPV- head and neck cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B91.
Abstract B93: Investigating the role of the hematopoietic-specific DNMT3A mutations in the aggressive phenotype of colon cancer
Authors: Feng Yang , Shabashvili Daniil E. , Posada Luisa M. , Krajcik Kathryn I. , Gunaratne Chamara , Guryanova Olga A. 
Published: June 2021

Abstract
Clonal hematopoiesis (CH) is a nonmalignant condition characterized by clonal expansion of one or few hematopoietic stem cells. CH is associated with advanced age and presence of presumed leukemic driver mutations, such as in the DNMT3A gene. Clinical studies show that presence of CH mutations in the bone marrow in patients with solid tumors is associated with unfavorable prognosis and shorter survival. Moreover, CH mutations are enriched in tumor-infiltrating leukocytes compared to peripheral blood. While these observations have profound clinical implications, the understanding of the relationship between mutations in the blood system and aggressive phenotype of solid tumors is still lacking. We hypothesized that bone marrow-derived cells harboring alterations in DNMT3A contribute to tumor-promoting microenvironment through immune imbalance. To this end, we established a mouse model of CH driven by Dnmt3a alterations and are investigating its effect on a well-established colitis-associated colon cancer model (CAC) as a prototypical solid tumor. Wild-type recipient mice were transplanted with bone marrow from animals with: a) heterozygous loss of Dnmt3a (Dnmt3a+/−); b) Dnmt3a R878H point-mutation (Dnmt3aRH); c) wild-type controls (Dnmt3a+/+). Since inflammation is known to promote tumorigenesis, we are testing the sensitivity of engrafted mice to experimental colitis induced by 2.5% dextran sulfate sodium salt (DSS) in drinking water. Animals of all 3 experimental groups will be co-housed to control for cage-to-cage variability in microbiota. We will use total body weight loss, histopathology of harvested colons (swiss roll method)/colitis scores, colon size, and appearance of intestinal contents as a readout for colitis severity. Next, we will investigate AOM/DSS-induced tumorigenesis in CH model, including tumor burden and extent of inflammation between experimental groups. Finally, we will characterize tumor-infiltrating leukocytes that contribute to aggressive CAC phenotype to identify immune populations that engender this tumor-modulating function, including epigenetic and gene expression profiles. Our goal is to understand the relationship between mutations in the blood system and aggressive phenotype of nonhematologic cancers and to nominate potential targets for therapeutic intervention.
Citation Format: Yang Feng, Daniil E. Shabashvili, Luisa M. Posada, Kathryn I. Krajcik, Chamara Gunaratne, Olga A. Guryanova. Investigating the role of the hematopoietic-specific DNMT3A mutations in the aggressive phenotype of colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B93.