bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 917: Functional blocking of CD5 on T cells to enhance the efficacy of therapeutic PD-1 blockade in treatment of mouse 4T1 breast tumors
Authors: Alotaibi Faizah , Rytelewski Mateusz , Figueredo Rene , Zareardalan1 Ronak , Vareki Saman Maleki , Zheng Xiufen , Zhang Meng , Ferguson Peter , El-Hajjar Mikal , Najajreh Yousef , Min Wei-ping , Koropatnick James 
Published: September 2020

Abstract
Blockade of programmed cell death protein 1 (PD-1) is approved for treatment of multiple human cancers and is the focus of multiple studies due to its key role in T cell function. However, only patients with ‘'hot'' tumors (i.e. those with increased numbers of tumor-infiltrating CD8+ T cells) respond well to the blockade. This suggests that new strategies to increase infiltration of CD8+ T cells into tumors will increase the number of tumor types and patients benefiting from anti-PD-1 therapy. CD5, a member of the scavenger receptor cysteine-rich (SRCR) superfamily, is expressed on T cells and a subset of B cells (B1a). It can attenuate TCR signaling and impair cytotoxic T lymphocyte (CTL) activation. CD5 knockout mice have increased anti-tumor immunity and reduced homograft tumor growth: reducing CD5 on CTLs may be therapeutically beneficial to enhance the anti-tumor response and increase tumor-infiltrating CD8+ T cells. We report that in vivo administration of anti-CD5 blocking MAb treatment increased primary T cell activation in response to 4T1 tumor cell homografts and ex vivo activation as measured by increased CD69, Fas, Fas ligand, IFNγ, PD-1, and apoptosis. Further, anti-CD5 treatment enhanced the capacity of primary T cells to kill 4T1 tumor cells ex vivo. Mice receiving anti-CD5 and anti-PD-1 in combination exhibited increased overall survival compared to mice treated with either agent alone. These data support the potential of blockade of CD5 function to enhance T cell-mediated anti-tumor immunity and PD-1 blockade treatment.
Citation Format: Faizah Alotaibi, Mateusz Rytelewski, Rene Figueredo, Ronak Zareardalan1, Saman Maleki Vareki, Xiufen Zheng, Meng Zhang, Peter Ferguson, Mikal El-Hajjar, Yousef Najajreh, Wei-ping Min, James Koropatnick. Functional blocking of CD5 on T cells to enhance the efficacy of therapeutic PD-1 blockade in treatment of mouse 4T1 breast tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 917.
Abstract 921: TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy
Authors: Gonzalez Caleb , Williamson Sarah , Gammon Seth , Piwnica-Worms David 
Published: September 2020

Abstract
Despite the success of immune checkpoint therapies (ICT) in achieving durable responses in subsets of cancer patients, not all patients respond to these types of therapies. Primary and adaptive resistance to immunotherapies present a considerable obstacle in achieving enhanced survival in a broader population of patients. Innate immune activators have been actively pursued for their antitumor potential. Herein, we report that a syngeneic 4T1 mammary carcinoma murine model for established highly refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with the TLR5 agonist flagellin, in combination with intra-peritoneal antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive components of the immune system. Of note, low serum levels of G-CSF at weeks 6 and 7 correlated highly with enhanced survival at week 18 (Hazzard Ratio 11, p &lt; 0.01, n=11). Furthermore, we also observed enhanced survival with combination TLR5 agonist plus ICT in the poorly immunogenic B16-F10 melanoma tumor model. Combination immune checkpoint therapy plus innate immune activation with TLR5 agonists may offer a new therapeutic strategy to treat ICT-refractory solid tumors.
Citation Format: Caleb Gonzalez, Sarah Williamson, Seth Gammon, David Piwnica-Worms. TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 921.
Abstract 934: “GPCR-ome” modulation upon PD1 / PDL1 axis blockade
Authors: Nafia Imane , Leroy Xavier , Cerf Loic , Guegan Jean-Philippe , Blayo Anne-Laure , Italiano Antoine , Schann Stephan , Bessede Alban 
Published: September 2020

Abstract
Background: Immunotherapy represents a novel weapon within the cancer armamentarium with unprecedented response observed in several indications including among others metastatic melanoma and Lung cancer. However, the limited rate of response accounting for app. 30% requires further optimization and thus calls the interest in elucidating mechanisms underlying sensitivity to immune checkpoint inhibitors. G Protein-Coupled Receptors (GPCRs) are the largest gene family of cell membrane-associated molecules mediating signal transmission, involved in several physiological functions including the shaping of the immune response but their role in tumor biology and particularly in immune evasion and resistance to immunotherapy remains to be elucidated
Methods: Using a preclinical syngeneic mouse model of sarcoma based on the inoculation of murine sarcoma MCA205 cell line, we investigated - besides the evaluation of tumor growth and survival - a large set of GPCRs upon PDL1 or PD1 blockade. Gene expression analysis was performed on tumor samples by mean of RNA sequencing. Data were analyzed using computational methodology including CIBERSORT and GSEA algorithms to evaluate immune cell subset within the tumor and specific gene datasets enrichment respectively. A large set of GPCRs (1412 in total) was then investigated through conventional Differential Gene Expression (DGE) analysis.
Results: PDL1/PD1 axis blockade, using specific antibodies, exhibited a strong anti-tumor effect. As highlighted by CIBERSORT analysis, anti-PD1/PDL1 antibodies triggered a CD8 and activated NK cells infiltration within the tumor. The recruitment of such effectory populations was associated with enrichment in genes from different hallmarks datasets including allograft rejection and interferon signaling thus confirming the induction of an efficient anti-tumor immune response. Concomitantly, this study revealed a significant up-regulation of several GPCRs already known to be involved in immune evasion - including Adenosine, Prostaglandins and chemokines receptors - but also highlighted the modulation of unexpected orphan or peptidic receptors. Altogether, this novel dataset confirms the induction of an effective anti-tumor immune response upon PD1 / PDL1 blockade and highlights the modulation of GPCRs that warrants further investigation to delineate their exact participation in sensitivity to immunotherapy.
Citation Format: Imane Nafia, Xavier Leroy, Loic Cerf, Jean-Philippe Guegan, Anne-Laure Blayo, Antoine Italiano, Stephan Schann, Alban Bessede. “GPCR-ome” modulation upon PD1 / PDL1 axis blockade [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 934.
Abstract 942: HPK1, hematopoietic progenitor kinase 1, is a promising therapeutic target for cancer immunotherapy
Authors: Ciccone David , Rocnik Jennifer , Lazari Vad , Linney Ian , Briggs Michael , Collis Alan , Loh Christine , Ashwell Mark , Montana John , Tummino Peter , Kaila Neelu 
Published: September 2020

Abstract
Introduction: HPK1, a member of the MAP4K family of protein serine/threonine kinases, is involved in regulating signal transduction cascades in cells of hematopoietic lineage. Recent data from HPK1 knockout animals and kinase-inactive knock-in animals underscores the role of HPK1 in negatively regulating lymphocyte activation. This negative-feedback role of HPK1 downstream of lymphocyte activation and function combined with its restricted expression in cells of hematopoietic origin make it an ideal drug target for enhancing anti-tumor immunity.
Experimental Procedures: A structure-based drug design approach was used to identify potent and selective inhibitors of HPK1. Various biochemical and biophysical assays, as well as a primary in vitro T cell activation assay, were utilized for multiple rounds of structure-activity relationship (SAR) studies. In vivo target engagement and pharmacodynamic data were generated using an anti-CD3 mouse model.
Results: In vitro, HPK1 small molecule inhibition resulted in enhanced IL-2 production in primary mouse T cells and in purified human T cells stimulated with a suboptimal dose of anti-CD3/anti-CD28. Increased selectivity of HPK1 inhibitors relative to T cell-specific kinases and within the MAP4K family was responsible for further enhancing the IL-2 response in activated T cells. In vivo, qd oral dosing of an HPK1 inhibitor completely abrogated phosphorylated SLP-76, induced by administration of anti-CD3. Furthermore, inflammatory cytokine production was enhanced in vivo upon HPK1 inhibition.
Conclusion: Pharmacological blockade of HPK1 kinase activity represents a novel and powerful immunomodulatory approach for anti-tumor immunity.
Citation Format: David Ciccone, Jennifer Rocnik, Vad Lazari, Ian Linney, Michael Briggs, Alan Collis, Christine Loh, Mark Ashwell, John Montana, Peter Tummino, Neelu Kaila. HPK1, hematopoietic progenitor kinase 1, is a promising therapeutic target for cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 942.
Abstract 945: Advancing cancer immunotherapeutics: A focus on characterization of anti-CTLA-4 mAbs for better anti-tumor immunity and less toxicity
Authors: Du Xuexiang , Liu Mingyue , Zhang Yan , Tang Fei , Ai Chunxia , Zhang Peng , Zheng Pan , Liu Yang 
Published: September 2020

Abstract
Anti-CTLA-4 monoclonal antibodies confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAEs). How to uncouple the undesired irAEs from the beneficial CITE seen in cancer patients treated with anti-CTLA-4 and/or other checkpoints inhibitors has proven to be a daunting challenge, partially due to the lack of the understanding of the real MOA(mechanism of Action) of CITE and irAEs. Meanwhile, an animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. We not only discovered that the immunotherapy of current anti-CTLA-4 mAbs were dependent on Fc/Fc receptor mediated intra-tumor Treg depletion rather than the widely held mechanism of checkpoint blockade, which raised the reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy, we also establish one realistic irAEs model and find one mechanism of irAEs. In this model, the clinically used drug Ipilimumab (or TremeIgG1) induced severe irAEs especially when combined with an anti-PD-1 antibody; whereas another mAb L3D10 induced comparable CITE with very mild irAE under the same conditions. Humanization (HL12/HL32) of L3D10, which led to the loss of blocking activity, further increased safety without affecting the therapeutic effect. Furthermore, we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.
Citation Format: Xuexiang Du, Mingyue Liu, Yan Zhang, Fei Tang, Chunxia Ai, Peng Zhang, Pan Zheng, Yang Liu. Advancing cancer immunotherapeutics: A focus on characterization of anti-CTLA-4 mAbs for better anti-tumor immunity and less toxicity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 945.
Abstract 965: Eribulin promotes a distinct immunogenic gene expression signature as compared with paclitaxel
Authors: Fermaintt Charles , Mooberry Susan , Risinger April L. 
Published: September 2020

Abstract
Microtubule targeted agents (MTAs) are a mainstay in the treatment of breast cancer and they are often used in combination with targeted agents, including immunotherapies. Although patients with triple-negative breast cancers (TNBCs) have historically had poorer clinical outcomes due in part to a lack of targeted therapeutic options, these cancers are often more immunogenic than other types of breast cancer. Recently, the combination of the PD-L1 inhibitor atezolizumab with the taxane nab-paclitaxel was found to prolong progression-free survival in patients with metastatic TNBC. Other combinations of MTAs and immune checkpoint inhibitors are actively being evaluated in clinical trials. There is a mechanistic rationale for this combination because paclitaxel is a direct TLR4 agonist that promotes activation of the innate immune system. To date, there has not been a comprehensive comparison of the immunomodulatory effects of different MTAs on immune cells or on or TNBC cells. We hypothesized that MTAs that differentially alter interphase microtubule structure and dynamics would have distinct effects on cell-intrinsic immunogenic pathways and that these effects could impact the efficacy of these drugs in combination with immunotherapies. The effects of 5 MTAs used for the treatment of TNBC, paclitaxel, docetaxel, ixabepilone, vinorelbine, and eribulin, on the expression of antitumor cytokines and other immunomodulatory genes in myeloid and TNBC cells was evaluated. Our results show that the TLR4-mediated induction of TNFα that occurs in response to paclitaxel was not observed with either eribulin or vinorelbine. Conversely, upregulation of type 1 interferons and interferon-stimulated genes (ISGs) was observed in monocytes and in bone-marrow derived macrophages within 6 h of treatment with eribulin or vinorelbine, but not with any of the microtubule stabilizers. Eribulin-mediated induction of type 1 interferons was also observed in a subset of eribulin-treated TNBC cells and was independent of its antimitotic effects. Importantly, type I interferon signaling has been shown to enhance the efficacy of immune checkpoint inhibitors, suggesting that microtubule destabilizers could have distinct advantages as compared to microtubule stabilizers in combination with these agents. Together, these results provide evidence that MTAs have different immune modulatory properties and suggest that the specific immune signatures initiated by different MTAs need to be considered for their optimal use with targeted agents, including checkpoint inhibitors. These studies were funded by Eisai.
Citation Format: Charles Fermaintt, Susan Mooberry, April L. Risinger. Eribulin promotes a distinct immunogenic gene expression signature as compared with paclitaxel [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 965.
Abstract 97: Analysis of Pten-null mouse astrocytes revealed overlapping transcribed genes with human glioblastoma transcriptome
Authors: Liu Tian , Or Penelope Mei-Yu , Wong Chi-Wai , Cheung Stanley Kwok-Kuen , Wang Yubing , Wang Yiwei , Chan Andrew M. 
Published: September 2020

Abstract
Glioblastoma is an aggressive form of brain cancer with universally poor prognosis. Even with optimal therapy, the cancer recurs frequently. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene whose mutations are often found in multiple human cancers. PTEN encodes a lipid phosphatase and serves as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway. Cumulative evidence suggests that PTEN mutations play significant roles in tumorigenesis of glioblastoma as 60% of glioblastoma patients acquired mutations in this gene. Based on our preliminary data, transcriptomic profiling of primary astrocytes derived from Pten knockout mice revealed an overlapping enrichment of mitotic regulators and cell cycle related pathways with human GBM. 4 genes (RCC1, RCC2, NEK2, and CHK2) were validated to be significantly upregulated in PTEN KO astrocytes by qRT-PCR. Regulator of chromatin condensation 2 (RCC2) has been reported to be guanine-nucleotide exchange factor (GEF) for Rac1 and RalA GTPase and act as a regulator of cell cycle progression. Accumulating evidence revealed a pro-tumorigenic role of RCC2 in multiple cancers such as tumor growth and tumor metastasis. Via siRNA inhibition of RCC2, we demonstrated that knocking down of RCC2 in glioblastoma cell lines suppresses cell growth and RCC2 is essential for both G1-S and G2-M progression. Additionally, RCC2 knocking down and a PI3K inhibitor LY294002 inhibit glioblastoma cell viability in a synergistic manner. In summary, PTEN deficiency leads to the upregulation of RCC2, which may promote tumorigenesis of glioblastoma by dysregulating cell cycle progression.To further explore the RCC2 roles, we will find the potential downstream target of RCC2 in dysregulating cell cycle and its potential therapeutic effect in vivo. Funding: General Research Fund Grant #14113519 from The Research Grants Council of Hong Kong
Citation Format: Tian Liu, Penelope Mei-Yu Or, Chi-Wai Wong, Stanley Kwok-Kuen Cheung, Yubing Wang, Yiwei Wang, Andrew M. Chan. Analysis of Pten-null mouse astrocytes revealed overlapping transcribed genes with human glioblastoma transcriptome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 97.
Abstract 973: Telomere stress potentiates host STING-dependent anti-tumor immunity
Authors: Zhang Anli , Mender Ilgen , Ren Zhenhua , Han Chuanhui , Deng Yafang , Siteni Silvia , Li Huiyu , Shay Jerry W. , Fu Yang-Xin 
Published: September 2020

Abstract
Telomerase is an attractive target for anti-tumor therapy as it is almost universally expressed in cancer cells but not in normal cells. Here we show that treatment with a telomerase-mediated telomere-targeting drug, 6-thio-2'-deoxyguanosine (6-thio-dG), leads to tumor regression in innate and adaptive immune-dependent manners in syngeneic and humanized mouse colon cancer models. 6-thio-dG treatment causes telomere-associated DNA damages that are sensed by dendritic cells (DCs) and activates the host cytosolic DNA sensing STING/IFN-I pathway, resulting in enhanced cross-priming capacity of DCs and tumor-specific CD8 T-cell activation. Moreover, 6-thio-dG overcomes resistances to checkpoint blockade in advanced mouse cancer models. Together, our results unveil how 6-thio-dG induced telomere stress increases innate sensing and adaptive anti-tumor immunity and provide a strong rationale for sequentially combining telomerase directed telomere-targeted therapy with immunotherapy.
Citation Format: Anli Zhang, Ilgen Mender, Zhenhua Ren, Chuanhui Han, Yafang Deng, Silvia Siteni, Huiyu Li, Jerry W. Shay, Yang-Xin Fu. Telomere stress potentiates host STING-dependent anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 973.
Abstract 976: The systematic identification of novel immune checkpoint averting the metastasis of ovarian cancer: The role of IL20/IL24-IL20RA axis
Authors: Li Jia , Xuan Qin , SHI JIE , Wang Longlong , Shi Yi , Xiang Rong 
Published: September 2020

Abstract
Ovarian cancer has high mortality among all gynecological malignancies due to the lack of clear symptoms at early stage and the metastasis of cancer cells when diagnosed with advanced stage. The disseminated ovarian cancer cells have to overcome the immune surveillance in abdominal environment, which are rich in many types of immune cells, to survive and proliferate. However, the key genes and mechanisms preventing the metastasis of ovarian cancer cells into abdominal sites keep largely unexplored. Here, through an in vivo, genome-scale CRISPR/Cas9 knockout screening, we identified IL-20/IL24-IL20RA as a key checkpoint preventing the abdominal metastasis of ovarian cancer cells. In ovarian cancer patients, the level of IL20RA is dramatically decreased in metastatic cancer cells when compared with that in primary sites. Overexpression of IL20RA in highly metastatic ovarian cancer cells greatly suppressed the abdominal metastasis of ovarian cancer and the formation of ascites. In contrast, silencing IL20RA could increase the metastasis of ovarian cancer cells. We further examined IL20RA mediated crosstalk between the disseminated cancer cells and the immuno-microenvironment in mouse in vivo ovarian cancer models and in vitro co-culture experiments. Silencing IL20RA in ovarian cancer cells resulted in a dramatic decrease of M1 subtype of macrophages and increase of the M2 subtype of macrophages without affecting the population of T and B lymphocytes in ascites. Further mechanistic studies revealed that the ovarian cancer cells, when invaded into the abdominal sites, greatly induced the mesothelial cells in peritoneum to produce IL20RA ligands, i.e., IL-20 and IL-24, which in turn activated the IL20RA downstream signaling in ovarian cancer cells to trigger the production and maturation of IL-18. IL-18, when secreted into the microenvironment, was able to promote the polarization of macrophages into M1-subtype to clear the cancer cells. Thus, we identified a novel immune checkpoint IL-20/IL24-IL20RA that was always downregulated in metastatic ovarian cancer cells to prevent the formation of an anti-tumor immune microenvironment, which could be utilized to develop new strategies for the immunotherapy of ovarian cancers.
Citation Format: Jia Li, Qin Xuan, JIE SHI, Longlong Wang, Yi Shi, Rong Xiang. The systematic identification of novel immune checkpoint averting the metastasis of ovarian cancer: The role of IL20/IL24-IL20RA axis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 976.