bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5565: Analysis of immune landscape in hepatocellular carcinoma patients with MDM2/4 mutations
Authors: Wang Xinjun , Zhang Hushan , Yang Yuan , Du Hang , Tang Jingling 
Published: June 2022

Abstract
Background Previous studies indicated that alteration of MDM2/4 was related to poor response even hyper-progressive disease (HPD) to immune checkpoint inhibitors (ICI) therapy. Meanwhile, ICI monotherapy showed low effective rate in hepatocellular carcinoma (HCC), it is still unclear that whether it was associated with HPD-related gene mutation such as MDM2/4. Herein, we analyzed characteristic of MDM2/4 mutation in HCC from tumor immune microenvironment (TIME), to explore the underlying mechanism.
Methods Gene mutation of 2615 patients with HCC was analyzed by next generation sequencing (NGS) in 3D Medicines, a laboratory accredited by CAP and Clinical Laboratory Improvement Amendments (CLIA), from Octomber 2017 to May 2020, 68 tumor tissue samples were collected for analysis of TIME, including CD8+ T cells, CD68+HLA-DR+ M1 macrophages and CD68+HLA-DR- M2 macrophages, CD56bright and CD56dim NK cells infiltrated in the tumor tissue, which were detected by multiple fluorescence immunohistochemistry (mICH).
Results Among these patients with HCC, 19.54% (511/2615) were mutated in gene MDM2/4, 18.9% (493/2165), 0.7% (18/2165) were MDM2 and MDM4, respectively. The 68 samples were divided into two groups, including group with wild type MDM2/4, and group with MDM2/4 alterations. Analysis of immune cell infiltration revealed that almost all of these immune cells we detected were less infiltrated into tumor tissue of patients with MDM2/4 mutation than without MDM2/4 mutation. What’s more, the most significant difference between patients with and without MDM2/4 alteration was infiltration of CD56dim NK cells (p&lt;0.001).
Conclusion The poor response to ICI monotherapy may associated with the high proportion of alteration in gene MDM2/4, which was characterized by low infiltration of immune cells, especially effective NK cells.
Citation Format: Xinjun Wang, Hushan Zhang, Yuan Yang, Hang Du, Jingling Tang. Analysis of immune landscape in hepatocellular carcinoma patients with MDM2/4 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5565.
Abstract 5596: TNFα production by myeloid DCs in response to rituximab induces monocyte and NK cell proliferation and survival
Authors: Yu Nanmeng , Weiner George J. 
Published: June 2022

Abstract
Background: Rituximab is a central component of chemoimmunotherapy for B cell lymphomas. With over two decades in clinical use, new insights into its mechanisms of action continue to emerge. Rituximab infusion into patients results in elevated levels of TNFα in patient sera. However, our understanding of the mechanism of TNFα production in the context of rituximab and its role in anti-tumor immunity remain limited. In our study, we sought to determine the major producers of TNFα following rituximab treatment and the effect of rituximab-induced TNFα on anti-tumor effector cells.
Methods: Peripheral blood mononuclear cells (PBMCs) from normal donors were cocultured in vitro with CD20-expressing Raji cells for 1 to 7 days. The coculture was treated with rituximab or non-specific antibody trastuzumab. Recombinant TNFα or TNFα blocking antibody infliximab were used to test the effect of TNFα in the rituximab- or trastuzumab-treated coculture system. ELISA was used to evaluate TNFα production in culture supernatant. Multicolor flow cytometry was used to evaluate for phenotypic and functional changes with TNFα treatment or blockade in various immune cell populations.
Results: TNFα was robustly produced by PBMCs when treated with rituximab. This production was mediated by the Fc portion of rituximab antibody, as rituximab Fab elicited very little if any TNFα response from PBMCs. Myeloid dendritic cells (HLA-DR+CD123-CD11c+) were the key producers of TNFα in response to rituximab. In the absence of antibody therapy, recombinant TNFα treatment induced proliferation and survival of two major effector cells in the peripheral blood: monocytes and NK cells as determined by cell count and percent of Ki67+ cells. TNFα blockade using infliximab inhibited monocyte and NK cell proliferation and survival. TNFα blockade also protected Raji cells from rituximab-mediated killing.
Conclusions: Rituximab-induced TNFα production promotes the proliferation and survival of monocytes and NK cells. Myeloid dendritic cells are necessary for TNFα production in this context. These results highlight the complexity of the immune response to rituximab treatment. Additional studies are ongoing exploring the role TNFa plays in the therapeutic response to rituximab.
Citation Format: Nanmeng Yu, George J. Weiner. TNFα production by myeloid DCs in response to rituximab induces monocyte and NK cell proliferation and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5596.
Abstract 5599: A novel orally available anti-cancer drug candidate, SB17170, represses myeloid-derived suppressor cells by targeting HMGB1
Authors: Choi Young Il , Ahn Sungoh , Kim Hyo Young , Jung Na Jin , Lee Jae Jin , Park Seung Bum 
Published: June 2022

Abstract
Introduction: High Mobility Group Box1 (HMGB1) is a kind of DAMP to modulate immune responses in various conditions, including the tumor microenvironment. In various cancers, it has been reported that cytoplasmic localization of HMGB1 is correlated with poor prognosis. Here, we present a novel small-molecule drug candidate, SB17170, which inhibits immune-suppressive cells in tumor microenvironments by specific binding to HMGB1.
Methods: SB17170 is a pro-drug of active metabolite SB1703 which was identified in cell-based phenotypic screening. SB1703 modulates immune responses by inhibiting the secretion of various cytokines from activated macrophages. HMGB1 was revealed as the target protein of SB1703 using Fluorescence difference In Two-dimensional Gel-Electrophoresis (FITGE). The antitumor activity of SB1703 was analyzed in B16F10 murine syngeneic model.
Results: SB17170 is orally available drug candidate at the clinical development stage for solid tumors. The active metabolite SB1703, bound to HMGB1, was observed in activated MDSC, but not in immature MDSC, and inhibited the activity and cytokine release of MDSC at the submicromolar range. The antitumor activity of SB17170 was observed in B16F10 murine syngeneic model, but not in immunodeficient NOG model, suggesting that SB17170 requires the adaptive immune system for its antitumor activity. The oral treatment of SB17170 in tumor-bearing mice induced intratumor T cell infiltration, but reduced the number of MDSC from day 3. SB17170 also repressed HMGB1 levels as well as MDSC in the blood. In combination with immune checkpoint inhibitors against PD1, PD-L1, and CTLA4, SB17170 enhanced the antitumor responses.
Conclusions: We presented here orally available small-molecule drug candidate, SB17170, which selectively binds to HMGB1 and represses MDSC in tumor microenvironment. SB17170 showed the antitumor activity in B16F10 murine syngeneic models, but not in immunodeficient background, suggesting that its mechanism of action is based on antitumor immune responses.
Citation Format: Young Il Choi, Sungoh Ahn, Hyo Young Kim, Na Jin Jung, Jae Jin Lee, Seung Bum Park. A novel orally available anti-cancer drug candidate, SB17170, represses myeloid-derived suppressor cells by targeting HMGB1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5599.
Abstract 56: MSK-ACCESS Heme: A cell-free DNA next-generation sequencing assay to identify somatic alterations in patients with lymphoma
Authors: DiNapoli Sara E. , Spence Coleman , Gedvilaite Erika , Bowman Anita , Diosdado Monica , Razumova Anna , Tsui Dana , Salles Gilles A. , Batlevi Connie , von Keudell Gottfried , Ptashkin Ryan , Zehir Ahmet , Berger Michael , Brannon A Rose , Benayed Ryma , Arcila Maria 
Published: June 2022

Abstract
Next-generation sequencing of cell-free DNA (cfDNA) can be used to noninvasively assess and monitor patients with lymphoma. Here, we describe the preliminary validation of MSK-ACCESS Heme (Memorial Sloan Kettering-Analysis of Circulating cfDNA to Examine Somatic Status), a cfDNA assay that employs unique molecular indexing and ultra-deep sequencing to detect somatic alterations in 117 genes related to hematologic malignancies. To our knowledge, this is the first report of a clinical-grade cfDNA assay developed specifically for hematologic malignancies.
Overall assay performance was assessed using 53 validation samples (26 normal samples and 27 cfDNA samples with somatic variants). Initial accuracy studies showed excellent correlation with the reference next-generation sequencing method (MSK-ACCESS Solid), detecting 32/32 (100%) of expected variants with a variant allele frequency over 1%. The limit of detection was assessed using standard samples, with detection of variants down to 0.5% variant allele frequency. Results were highly concordant in both inter- and intra-assay reproducibility studies.
Overall, these data indicate that MSK-ACCESS Heme is a robust cfDNA-based assay that can be used to detect variants at low frequency with high reproducibility. Future work sequencing additional samples will be performed to further assess the performance of the panel.
Citation Format: Sara E. DiNapoli, Coleman Spence, Erika Gedvilaite, Anita Bowman, Monica Diosdado, Anna Razumova, Dana Tsui, Gilles A. Salles, Connie Batlevi, Gottfried von Keudell, Ryan Ptashkin, Ahmet Zehir, Michael Berger, A Rose Brannon, Ryma Benayed, Maria Arcila. MSK-ACCESS Heme: A cell-free DNA next-generation sequencing assay to identify somatic alterations in patients with lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 56.
Abstract 5620: CD34+humanized huHSC-NCG mice engrafted with hematological malignancies models for preclinical study of anti-human CD19 therapeutic antibodies
Authors: Yu Weiwei , Ju Cunxiang , Sun Hongyan , Zhang Mingkun , Bao Honghong , Li Shuai , Ju Chao , Zhao Jing , Gao Xiang 
Published: June 2022

Abstract
CD19, has become a vital immune and cellular therapeutic target to treat B-cell malignancies, as anti CD19 antibodies has produced remarkable clinical outcomes. Due to the lack of functional murine T cells, as well as B and NK cells, NCG mice engrafted with CDX or PDX models are well suited for evaluating CAR-T anti-tumor efficacy, but do not meet the needs of evaluating in vivo anti-tumor efficacy of anti-human CD19 bispecific or tri-specific antibodies that require functional human T cells.huHSC-NCG mice were established by the engraftment of CD34+ hematopoietic stem cells (HSC) into irradiated NCG mice. Among multi-lineages of human immune cells, the level of reconstituted human CD3+ T cells gradually increased in huHSC-NCG mice from 10 weeks after engraftment for long-term efficacy evaluation study. Both CD8+ cytotoxic and CD4+ helper T lymophocytes were detected by FACS in blood circulation. In this study, we established mice engrafted with Raji-Luciferase lymphoma and orthotopically engrafted with Nalm6-Luciferase leukemia cells. Both Blinatumomab and tri-specific antibodies displayed a pharmacological effect by reducing the proportion and total counts of B cells in circulation, showed significant tumor growth inhibition and prolonged the survival of xenograft huHSC-NCG mice. Taken together, huHSC-NCG mice is an ideal mouse model for preclinical study of bi-specific or tri-specific T cell engager therapeutic antibodies.
Citation Format: Weiwei Yu, Cunxiang Ju, Hongyan Sun, Mingkun Zhang, Honghong Bao, Shuai Li, Chao Ju, Jing Zhao, Xiang Gao. CD34+humanized huHSC-NCG mice engrafted with hematological malignancies models for preclinical study of anti-human CD19 therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5620.
Abstract 5626: Acquisition of lymphatic phenotype in bone marrow endothelial progenitors is regulated by immunosuppressive Th2 cytokines
Authors: Gonzalez Maria Espinoza , Volk-Draper Lisa , Bhattarai Nihit , Ran Sophia 
Published: June 2022

Abstract
Introduction: Myeloid-lymphatic endothelial progenitors (M-LECPs) significantly contribute to expansion of tumor lymphatics and metastasis to lymph nodes. Bone marrow (BM) generated M-LECPs are a subset of M2-type of tumor-associated macrophages (TAMs) that heavily infiltrate breast and other human cancers. The M2-type of TAMs is primarily induced by immunosuppressive Th2 cytokines IL-4, IL-13, and IL-10. The goal of this study was to determine whether Th2 factors also promote the lymphatic phenotype in precursors of M-LECPs.
Methods: Mouse BM cells were differentiated into M-LECPs by priming with CSF-1 followed by activation of LPS-TLR4 pathway. Transcripts of IL-4, IL-13, and IL-10 were measured by qPCR, and their proteins secreted into conditioned medium were detected by ELISA. The levels of receptors for Th2 cytokines IL-4, IL-13, and IL-10 as well as for stem cells (CD117, Sca-1), M2-TAMs (CD204, CD206) and lymphatic endothelial cells (Lyve-1, podoplanin, integrin-9a, collectin-12 and stabilin-1) were quantified by qPCR and flow cytometry. Impact of TLR4 induced autocrine IL-10 pathway was determined by analyzing the surface markers and gene profiles of differentiated M-LECPs in the presence of IL-10 blocking or control antibodies. Tumor levels of Th2 cytokines and expression of Th2 receptors in Lyve-1+ progenitors were detected by ELISA and immunofluorescence, respectively.
Results: More than 95% of myeloid precursors treated with CSF-1 and LPS upregulated all three Th2 receptors and IL-10 but not IL-4 or IL-13 ligands. All receptors were functional as indicated by upregulation of M2, immunosuppressive, lymphatic and stem markers in cells co-treated with exogenous Th2 ligands as compared with CSF-1 alone. Blocking autocrine IL-10 significantly suppressed both M2-specific and pro-lymphatic differentiation. Tumor-infiltrating M-LECPs expressed Th2 receptors as well as all corresponding ligands including IL-4 and IL-13 that were absent in the BM cells.
Conclusion: These data present a novel evidence that activation of immunosuppressive Th2 pathways in BM myeloid precursors induces both the M2-type and lymphatic phenotype. Expansion of lymphatics can enhance tumor immunosuppression by physical removal of immunostimulatory cells. These findings suggest that targeting Th2 pathways can simultaneously relieve immunosuppression and inhibit differentiation of pro-lymphatic progenitors that promote metastasis.
Citation Format: Maria Espinoza Gonzalez, Lisa Volk-Draper, Nihit Bhattarai, Sophia Ran. Acquisition of lymphatic phenotype in bone marrow endothelial progenitors is regulated by immunosuppressive Th2 cytokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5626.
Abstract 5635: Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in KRAS-mutant cancer
Authors: Tanaka Kosuke , Morita Tomoko Yamamori , Hakozaki Yumi , Yoshiya Miyuki , Mashima Chiaki , Liu Jie , Kageyama Shun-ichiro , Ohashi Akihiro , Kobayashi Susumu 
Published: June 2022

Abstract
Although mitochondrial DNA (mtDNA) can stimulate innate immune response that potentiates the efficacy of cancer immunotherapy, how to maximize this innate immune system in certain cancer subtypes remains unknown. Here we show that mtDNA is enriched in KRAS-mutant tumor where the dsDNA-sensor machinery cGAS-STING signaling is autonomously activated at the baseline. Intriguingly, MEK inhibitor induces cytosolic mtDNA release to potently activate cGAS-STING pathway, that is counteracted by PRKN-mediated mitophagy to eliminate mtDNA within damaged mitochondria in KRAS-mutant tumor. Combined MEK and mitophagy inhibitors synergistically boost type I IFNs through mitochondrial stress and promote lymphocyte infiltration into the TME in a mtDNA efflux-dependent manner. Moreover, this combination enhances the efficacy of PD-1 blockade in KRAS-mutant tumor. PRKN clinically associates with KRAS/LKB1-mutant subtype, lower antigen-presenting signature, and ICB resistance. Together, targeting mtDNA renders promising strategy to enable cancer immunotherapy in KRAS-mutant cancers.
Citation Format: Kosuke Tanaka, Tomoko Yamamori Morita, Yumi Hakozaki, Miyuki Yoshiya, Chiaki Mashima, Jie Liu, Shun-ichiro Kageyama, Akihiro Ohashi, Susumu Kobayashi. Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in KRAS-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5635.
Abstract 5657: Anti-hypertensive drugs increase TRAIL sensitivity-induced surface DR5 via autophagy inhibition pathway in prostate cancer cells
Authors: park sang-youel , Kim Jong-Hun , Hong Jeong-Min , Seol Jae-Won 
Published: June 2022

Abstract
Angiotensin II type 1 receptor blockers(ARB) are used as antihypertensive agents, The cohort study found that among people with prostate cancer, thus taking Angiotensin II type 1 receptor blockers had reduced risk ratio. This study investigated that can ARB treatment enhance the TRAIL-mediated prostate cancer cell apoptosis, and the detailed molecular mechanisms. The results showed that ARB treatment increased the TRAIL-mediated prostate cancer cell apoptosis. In the mechanism study, ARB treatment increased DR5 protein expression level, surface DR5 protein amount, and DR5 protein stability. Furthermore, the Regulation of DR5 expression was mediated by autophagy flux inhibition followed by ARB treatment. Taken together, the results demonstrated that ARB treatment sensitized prostate cancer cells to TRAIL-induced apoptosis via autophagy inhibition and DR5 protein stabilization, and also suggest that the prostate cancer cells of ARB taken-patient may be sensitized to TRAIL-mediated apoptosis, and may support the mechanism of cohort study which showed reduction of prostate cancer risk ratio in patient taking angiotensin II type 1 receptor blockers.
Citation Format: sang-youel park, Jong-Hun Kim, Jeong-Min Hong, Jae-Won Seol. Anti-hypertensive drugs increase TRAIL sensitivity-induced surface DR5 via autophagy inhibition pathway in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5657.
Abstract 5674: A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis
Authors: Fan Li , Pan Qingfei , Yang Wentao , Koo Selene C. , Tian Cheng , Li Liyuan , Lu Meifen , Brown Anthony , Ju Bensheng , Easton John , Ranganathan Sarangarajan , Shin Soona , Bondoc Alexander , Yang Jun J. , Yu Jiyang , Zhu Liqin 
Published: June 2022

Abstract
Background and Rationale: Hepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigating whether the neonatal liver provides a protumorigenic niche to HB development.
Methods: HB development was compared between orthotopic transplantation models established in postnatal day 5 and 60 mice (P5Tx and P60Tx models). Single-cell RNA-sequencing was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival.
Results: We found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in metastatic HB patient tumors there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with HB patient prognosis among pediatric cancers.
Conclusion: We demonstrated that the neonatal liver provides a prometastatic niche to HB development via the Cxcl1/Cxcr2 axis.
Citation Format: Li Fan, Qingfei Pan, Wentao Yang, Selene C. Koo, Cheng Tian, Liyuan Li, Meifen Lu, Anthony Brown, Bensheng Ju, John Easton, Sarangarajan Ranganathan, Soona Shin, Alexander Bondoc, Jun J. Yang, Jiyang Yu, Liqin Zhu. A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5674.