bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3151: β Hydroxy β Methylbutyrate synergizes with cytotoxic chemotherapy and immunotherapy in a mouse model of pancreatic cancer
Authors: Coleman Michael F. , Liu Kristyn A. , Etigunta Suhas K. , Pfeil Alex J. , Tang Xiaohu , Fabela Salvador , Lashinger Laura M. , Cui Zhengrong , Hursting Stephen D. 
Published: July 2021

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) remains the 4th most deadly cancer in the US. Current chemotherapeutic regimens poorly control PDAC progression and no approved immunotherapeutic options currently exist. PDAC incidence and progression are increased by obesity, which promotes a potently protumor PDAC microenvironment characterized by inflammation, fibrosis, and immunosuppression. β Hydroxy β Methylbutyrate, found to be safe and well-tolerated in clinical trials over many years, blunts cancer cachexia; however it has not been tested in PDAC. Further, the role of HMB in modifying existing therapies has been understudied. We sought to determine if HMB treatment would alter therapeutic response of lean and obese mice to gemcitabine or anti-PD1 immunotherapy.
Methods: Lean and obese C57BL/6 mice were treated with HMB alone or in combination with gemcitabine or anti-PD1 immunotherapy following subcutaneous injection of Panc02 PDAC cells. In addition, bone marrow-derived macrophages (BMDM) were treated with HMB in vitro with or without LPS. Tumor/macrophage transcriptomic analysis, followed by gene set enrichment analysis and enrichment mapping identified transcriptional responses. CIBERSORTx determined microenvironment immune cell composition.
Results: a) HMB reduces obesity-associated PDAC progression; b) HMB treatment and gemcitabine together suppress PDAC growth in obese mice; c) HMB mitigates PDAC immunosuppression and promotes tumor immune surveillance; d) HMB enhances the efficacy of anti-PD1 immunotherapy; e) HMB promotes M1 polarization of BMDM.
Conclusion: Overall, HMB evokes antitumor immune responses in the context of pro-inflammatory stimuli such as obesity or immunotherapy. Moreover, HMB promotes immune surveillance in PDAC, synergizing with both cytotoxic chemotherapy and immunotherapy. HMB has been found to be safe and well tolerated in clinical trials for many years. Hence, HMB-induced suppression of PDAC tumor growth and promotion of immune surveillance may offer significant synergy with chemotherapies or immunotherapies in PDAC. This research was supported by R35CA197627 to S. Hursting.
Citation Format: Michael F. Coleman, Kristyn A. Liu, Suhas K. Etigunta, Alex J. Pfeil, Xiaohu Tang, Salvador Fabela, Laura M. Lashinger, Zhengrong Cui, Stephen D. Hursting. β Hydroxy β Methylbutyrate synergizes with cytotoxic chemotherapy and immunotherapy in a mouse model of pancreatic 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 3151.
Abstract 3156: Over-expression of CEACAM6 negatively modulates the tumor microenvironment in pancreatic cancer
Authors: Pandey Ritu , Chen Yuliang , Patil Mihir , Conway Patrick J. , Al-Khinji Aisha , Mahadevan Daruka 
Published: July 2021

Abstract
Background: CEACAM6 is a cell adhesion receptor of the Ig-family over-expressed exclusively in primates and human pancreatic ductal adenocarcinoma (PDA). It is present in all subtypes and is enriched classical activated stroma subtype. CEACAM6 has multifaceted roles in KRAS mutant PDA and is a poor prognostic maker (Pandey et al. Sci Rep 2019). We report here in PDA, high CEACAM6 modulates the tumor microenvironment with an immunosuppressive landscape.
Methods: RNA-Seq data of PDA patient samples from TCGA and GEO were obtained, normalized and log transformed for analysis. Tumor samples were stratified into cohorts of high and low CEACAM6. Pearson correlation coefficient is utilized to identify CEACAM6 correlated genes and enrichment of signaling pathways. The two cohorts were scored by ESTIMATE for stromal and immune population. Abundance of different cell populations were calculated utilizing MCPcounter and ConsensusTME methods. All analysis was performed using R (v 4.3).
Results: High CEACAM6 PDA samples had both stromal and immune components. Half of the high expressing samples had a higher immune score vs stromal score. The other half had both high or both low, immune and stromal score. Investigating the immune genes that are utilized for scoring, we found several immune genes differentially expressed in high CEACAM6 (up-regulated genes - ADAM8, IL2RG, LYZ, SELPLG involved in innate immunity) compared to low CEACAM6 samples. Genes under expressed in high CEACAM6 samples were CD27, NKG7, IL18RAP, LILRB1, KLKRK1 involved in promoting immune response and cell protection. Overall TCGA PDA samples have lower enrichment of immune cells compared to higher enrichment of fibroblasts, endothelial cells, macrophages, monocytes and dendritic cells. The NK cells are overall low in PDA but enriched in some lower CEACAM6 samples. Plasma cells, B-cells, CD8 cells, NK cells, Cytotoxic T-cells, Tγδ-cells have very poor representation in higher CEACAM6 samples but present in some low CEACAM6 expressing samples. Some of the TCGA PDA samples have T-reg cells but high CEACAM6 do not enrich of T-reg cells. High CEACAM6 samples are enriched for metabolic pathways.
Conclusions: CEACAM6 over-expressed in PDA have pathologic functions which include reshaping the stroma, suppressing host immunity and inhibiting apoptosis. An anti-CEACAM6 Mab increases apoptosis, necrosis and anti-tumor activity in PDA.
Citation Format: Ritu Pandey, Yuliang Chen, Mihir Patil, Patrick J. Conway, Aisha Al-Khinji, Daruka Mahadevan. Over-expression of CEACAM6 negatively modulates the tumor microenvironment in pancreatic 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 3156.
Abstract 3178: A research tool for elucidating the interaction between human mucin 16 (CA125) and immune cells in ovarian cancer
Authors: Lakatos Kornel , Krauledat Petra , Serrano German Gonzalez , Hansen Peter , Cramer Daniel William , Elias Kevin , Patankar Manish , Hoballah Jawad 
Published: July 2021

Abstract
CA125 represents the circulating subunit of the large transmembrane glycoprotein MUC 16. Elevated levels of CA125 are suggestive of ovarian cancer and the magnitude of elevation correlates with burden of disease. A rising CA125 level after treatment suggests cancer recurrence. Ovarian tumor cells produce and shed MUC 16 which can bind to certain peripheral immune cells. To study this, current techniques use labelled-fluorescent markers that bind to CA125 on cells and flow cytometry to detect mean fluorescence. A limitation is that this technique may not be able to distinguish low-binding events from autofluorescence. Our new technology improves the resolution for studying CA125 bound to immune cells by employing antibody-labelled gold nanoparticles with far-greater sensitivity than fluorescent markers. The cells are then examined using darkfied microscopy rather than flow, which also permits automated slide scanning and focusing for 3-dimensional counting. This enables both simultaneous use of fluorescent markers to identify the immune cell populations as well as automated image analysis to quantify the amount of bound CA125 on individual cells. Preliminary data show that MUC 16 is preferentially bound to NK and T cells in women with ovarian cancer compared to binding in healthy controls. These insights may help elucidate the function of CA125 in ovarian cancer and improve our understanding of immune-tumor interactions.
Citation Format: Kornel Lakatos, Petra Krauledat, German Gonzalez Serrano, Peter Hansen, Daniel William Cramer, Kevin Elias, Manish Patankar, Jawad Hoballah. A research tool for elucidating the interaction between human mucin 16 (CA125) and immune cells in ovarian 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 3178.
Abstract 3183: Adrenergic signaling augments cytotoxic T-cell anti-tumor function in p53-deficient head and neck cancer
Authors: Silverman Deborah , Leahey Sara , Akhter Shamima , Xie Tongxin , Wang Yunfei , Doordjuin Elien , Calin George , Myers Jeffrey , Hwu Patrick 
Published: July 2021

Abstract
Few advances have been made against head and neck cancers, in part because treatment efforts have focused on the epithelial component of these tumors. However, therapies targeting the microenvironment, including immune checkpoint blockade (ICB), also remain ineffective in the majority of head and neck cancers. Like some other immunotherapy-nonresponsive tumors, head and neck cancers develop a complex microenvironment heavily infiltrated by nerve fibers arising from the peripheral nervous system. Studies in multiple models have shown that the ablation of different portions of the peripheral nervous system prevents cancer development and progression. We recently showed that existing nerves sprout and undergo autonomic reprogramming to an adrenergic-like phenotype as a result of orchestrated microRNA (miRNA) shuttling from cancer cells to neurons, resulting in activation of transcriptional programs that establish new neuronal identity. Given that activated T-cell subsets express high levels of adrenergic receptors, we hypothesized that adrenergic signaling may also influence tumor-infiltrating T-cell function. We used novel murine models of OCSCC to discern the effect of adrenergic nerve signaling on immune infiltration and immunotherapy response and correlated our findings with data from patient cohorts using bulk and single-cell RNA sequencing. We found that adrenergic signaling acutely enhanced cytotoxic T-cell activity in patient-derived tumor/T-cell pairs, and we elucidated a p53-dependent mechanism underlying this effect. Ultimately, these results provide a striking contrast to the known role of adrenergic signaling in cancer development: although nerve-cancer crosstalk drives cancer aggression and progression, tumor innervation may also better enable the host immune response. Therapeutic approaches targeting this critical component of tumor biology may be useful to improve patients' survival, treatment responses, and quality of life.
Citation Format: Deborah Silverman, Sara Leahey, Shamima Akhter, Tongxin Xie, Yunfei Wang, Elien Doordjuin, George Calin, Jeffrey Myers, Patrick Hwu. Adrenergic signaling augments cytotoxic T-cell anti-tumor function in p53-deficient head and neck 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 3183.
Abstract 3190: PD-L1 protein expression in Middle Eastern breast cancer predicts favorable outcome in triple negative breast cancer
Authors: Al-Kuraya Khawla S. , Siraj Abdul K. , Parvathareddy Sandeep K. , Ahmed Saeeda , Benito Allianah , Iqbal Kaleem 
Published: July 2021

Abstract
Programmed cell death ligand 1 (PD-L1) has been shown to induce potent T-cell mediated anti-tumoral immunity. The significance of PD-L1 expression on prognosis of breast cancer remains controversial and its prevalence and prognostic value in breast cancer from Middle Eastern ethnicity is lacking. A total of 1003 unselected Middle Eastern breast cancers were analyzed for PD-L1 expression using immunohistochemistry. The association with clinico-pathological markers and impact on overall survival as well as recurrence free survival was determined. PD-L1 expression was seen in 32.8% (329/1003) cases. PD-L1 positivity was significantly associated with poor prognostic indicators such as younger patients (p = 0.0499), high grade tumors (p = 0025), ER negative (p &lt; 0.0001) and PR negative (p = 0.0001) status as well as high Ki-67 index (p &lt; 0.0001). We also found a significant association between PD-L1 expression and deficient mismatch repair protein expression (p = 0.0009). No association was found between PD-L1 expression and clinical outcome. However, on further subgroup analysis, PD-L1 expression was found to be an independent marker for favorable prognosis in triple negative breast cancer (TNBC) (Hazard ratio = 0.27; 95% confidence interval = 0.10 - 0.63; p = 0.0018). In conclusion, we demonstrated strong association between PD-L1 and MSI in Middle Eastern BC patients and showed that PD-L1 overexpression on tumor cells was an independent favorable prognostic factor in TNBCs from this ethnicity. Overall, these findings might help in the development of more appropriate treatment strategies for BC in Middle Eastern population.
Citation Format: Khawla S. Al-Kuraya, Abdul K. Siraj, Sandeep K. Parvathareddy, Saeeda Ahmed, Allianah Benito, Kaleem Iqbal. PD-L1 protein expression in Middle Eastern breast cancer predicts favorable outcome in triple negative breast 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 3190.
Abstract 3192: PD-L1 is an independent prognostic marker in Middle Eastern PTC and its expression is upregulated by BRAFV600E mutation
Authors: Masoodi Tariq , Siraj Abdul K. , Parvathareddy Sandeep Kumar , Pratheeshkumar Poyil , Divya Sasidharan Padmaja , Begum Rafia , Diaz Roxanne , Saravanan Thangavel , Al-Obaisi Khadija , Siraj Sarah , Azam Saud , Qadri Zeeshan , Al-Kuraya Khawla S. 
Published: July 2021

Abstract
Background: PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. This study was conducted to evaluate the prognostic significance of PD-L1 expression in a large cohort of Middle Eastern PTC patients and to explore correlation of PD-L1 and BRAFV600E mutations in PTC tumors and cell lines.
Methods: Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating BRAFV600E in PTC cell lines.
Results: PD-L1 over-expression was noted in 32.4% (473/1458) of cases and significantly associated with adverse clinico-pathological parameters such as tall cell variant, extra-thyroidal extension and lymph node metastasis. Importantly, PD-L1 was found to be an independent poorer prognostic marker. We also found PD-L1 to be significantly associated with BRAF mutation and patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival compared to patients with BRAF mutation alone. In vitro analysis showed high expression of PD-L1 in BRAF mutated PTC cell lines compared to BRAF wild-type cell line. Inhibition of BRAF using vemurafenib induced PD-L1 expression in BRAF mutated cell lines without affecting cell growth. Knockdown of PD-L1 in BRAF mutated cell lines significantly decreased the cell growth and induced apoptosis.
Conclusion: Our data suggests that PD-L1 might represent a useful prognostic marker in Middle Eastern PTC and PD-L1 inhibition could be a potential therapeutic option for aggressive PTC cancers, such as tall cell variant, BRAF mutation positive patients that are unresponsive to standard treatment.
Citation Format: Tariq Masoodi, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Poyil Pratheeshkumar, Sasidharan Padmaja Divya, Rafia Begum, Roxanne Diaz, Thangavel Saravanan, Khadija Al-Obaisi, Sarah Siraj, Saud Azam, Zeeshan Qadri, Khawla S. Al-Kuraya. PD-L1 is an independent prognostic marker in Middle Eastern PTC and its expression is upregulated by BRAFV600E mutation [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 3192.
Abstract 3193: Development and functional characterization of NC762, a novel therapeutic antibody targeting B7-H4, for the treatment of malignancies
Authors: Archer Kristina , Ceradoy Justine , Coupet Tiffany , Bosiacki Jason , Song Chang , Weiss Ido , Niu Sue , Obot Tete , Xu Jinglin , O'Neill Tom , Ferrell Alison , Abukharma Hasan , Cusumano Zac , Flies Dallas , Langermann Sol , Liu Linda N. 
Published: July 2021

Abstract
Human B7 homolog 4 (B7-H4) is a transmembrane protein in the B7 family of molecules that is expressed on tumor cells in the tumor microenvironment (TME). High protein expression on tumors and low expression on healthy tissue makes B7-H4 an attractive molecule for direct targeting with low off-target toxicity. NC762 is a humanized immunoglobulin gamma 1, kappa (IgG1κ) monoclonal antibody specific for human B7-H4 that is being developed for the treatment of cancer and demonstrates an excellent safety profile in IND-enabling studies. The IgG1κ region of NC762 contains three-point mutations (S239D/A330L/I332E a.k.a. DLE) which enhances binding to CD16a (FcγRIIIa) in order to increase antibody-dependent cellular cytotoxicity (ADCC) activity. NC762 binds to human B7-H4 on SKBR3 cells, a breast cancer cell line that endogenously expresses B7-H4 and induces in vitro ADCC activity. Despite the high homology, NC762 does not cross-react with rodent B7-H4, therefore, in vivo testing was performed in a humanized xenograft murine model in NSG mice, where NC762 restricted tumor growth in a dose-dependent manner. Depleting human natural killer (NK) cells prior to tumor inoculation reduced anti-B7-H4 parent antibody activity, supporting a role for NK-cell mediated ADCC in tumor growth retardation. However, in the absence of human PBMCs, NC762 also achieved significant anti-tumor activity. Furthermore, a mutant of NC762 with a low FcγR binding IgG1 domain showed similar activity as the DLE IgG1, demonstrating an ADCC-independent mechanism of tumor growth restriction mediated by B7-H4 mAb treatment. Together, these results indicate that even with the ADCC-enhanced IgG1κ region, NC762 is able to mediate ADCC-independent anti-tumor activity for the eradication of B7-H4 expressing tumors; and is expected to provide benefit in multiple oncology indications.
Citation Format: Kristina Archer, Justine Ceradoy, Tiffany Coupet, Jason Bosiacki, Chang Song, Ido Weiss, Sue Niu, Tete Obot, Jinglin Xu, Tom O'Neill, Alison Ferrell, Hasan Abukharma, Zac Cusumano, Dallas Flies, Sol Langermann, Linda N. Liu. Development and functional characterization of NC762, a novel therapeutic antibody targeting B7-H4, for the treatment of malignancies [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 3193.
Abstract 3199: In vitro killing assays for immuno oncology candidates
Authors: Janss Thibaut J. , Lamy Juliette , Arnold Johan , Boelen Ellen , Pattijn Sofie 
Published: July 2021

Abstract
The need to better understand the tumor microenvironment (TME) dictates the characterization of the cell types involved, the roles they play and how they respond to treatment. To develop better cancer immunotherapies, in vitro primary immune cell bioassays offer an early assessment of their effects on the various players of the TME. Cytotoxic cells are key players in the anti-tumor immune response. CD8+ T cells, also known as cytotoxic T lymphocytes, recognize and kill cells presenting antigens bound to MHC class I molecules, such as neoantigen present on the tumor cells. Activation of CD8+ T cells requires at least two signals from antigen presenting cells: binding of their T cell receptor (TCR) to the appropriate peptide presented on MHC I and co-stimulation by B7 binding to CD28. However, tumor environment developed different mechanisms to reduce this immune cell killing such as checkpoint inhibitors expression. In that case, the immune system will be dampened. A second type of cytotoxic cells, named Natural killer cells, are an innate immune cell type that plays an important role in anti-cancer immunity. NK cells target cells lacking MHC I expression, including cancer cells that have lost expression of MHC I. NK cells induce apoptosis in cancer cells via release of perforin and granzymes from granules, like CD8+ T cells. But here too, NK cells can be broken down by the tumor cells, notably by the PD1/PDL1 interaction. Increasing their efficacy as a therapeutic strategy has made the development of new therapeutics enhancing their anti-tumor response a priority. Those new therapeutics can have several shapes. The Antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the IgG1 isotypes is one of the mechanisms that can be applied by immunoglobulin-based therapeutics. Another way to increase the killing of cancer cells is to target tumor antigens expressed by those cells using for example bispecific molecules that will enhance on the other side the T cell activation. Using primary immune cells, in vitro bioassays were developed to better screen the potential effect of new therapeutics on immune cell killing activity. Their ability to increase or induce a cytotoxic activity and facilitate the anti-tumor immune response can as a result be assessed early in the drug development process.
Citation Format: Thibaut J. Janss, Juliette Lamy, Johan Arnold, Ellen Boelen, Sofie Pattijn. In vitro killing assays for immuno oncology candidates [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 3199.