bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3226: The IRF8-osteopontin-CD44 axis functions as an immune checkpoint to control CD8+ T cell activation and tumor immune evasion
Authors: Klement John D. , Paschall Amy V. , Redd Priscilla S. , Ibrahim Mohammed L. , Lu Chunwan , Yang Dafeng , Celis Esteban , Abrams Scott I. , Ozato Keiko , Liu Kebin 
Published: August 2019

Abstract
Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and only fraction of patients with responsive tumors have a durable response to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints may exist, particularly in cancers resistant to current ICI immunotherapy, such as colorectal cancer. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation in a peptide vaccine model and allowed allograft transplant tumor tolerance. These effects were associated with upregulation of the CTL surface marker CD44. However, analysis of chimeric mice with competitive reconstitution of wild type and IRF8 KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in CD11b+Ly6CloLy6G+ myeloid cells and OPN acted as a potent T cell suppressor. In vitro stimulation of CTLs in the presence of OPN resulted in decreased expression of activation markers CD69 and CD25 and inhibited proliferation and interferon gamma (IFNg) secretion. Expression of OPN was found to be upregulated in both myeloid cells and colon epithelial cells following silencing of IRF8 expression. IRF8 bound to the Spp1 promoter, which encodes OPN, to repress OPN expression in colon epithelial cells. Correspondingly, human colon carcinoma cells exhibited decreased IRF8 and increased OPN expression. These increased OPN levels inhibited human PBMC proliferation and IFNg secretion. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicates that myeloid and tumor cell-expressed OPN acts as a novel immune checkpoint to suppress T cell activation and confer host tumor immune tolerance. Blockade of this checkpoint may expand the pool of patients who may benefit from ICI immunotherapy.
Citation Format: John D. Klement, Amy V. Paschall, Priscilla S. Redd, Mohammed L. Ibrahim, Chunwan Lu, Dafeng Yang, Esteban Celis, Scott I. Abrams, Keiko Ozato, Kebin Liu. The IRF8-osteopontin-CD44 axis functions as an immune checkpoint to control CD8+ T cell activation and tumor immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3226.
Abstract 3235: Activation-inducible TNFR family receptor (AITR) signaling mediates the polarization of CD4+ T cells into Th1, Th2, and Th17, converts Treg to Teff and eradicates solid tumors
Authors: Kwon Byoung S. , Lee Seung J. , Kim Young H. , Lee Joong W. , Hwang Sun H. , Vinay Dass S. 
Published: August 2019

Abstract
AITR (activation-inducible TNFR family receptor, human GITR), an inducible costimulatory receptor of human T cells, is expressed constitutively on Treg and inducible on Teff upon antigen engagement. AITR co-stimulates T cell activation and recruits certain members of TRAF family upon interaction with its ligand. We examined whether the stimulation of distinct regions of extracellular domain of AITR can generate signals that promote different subsets of CD4+ T cells. We found that crosslinking AITR by agonistic anti-AITR Abs (A27, A41, and A35), that recognize three distinct regions of the extracellular domain, polarize CD4+ T cells into Th1, Th2 and Th17, respectively. The subset polarization evoked by these antibodies was the result of recruitment of specific TRAFs, phosphorylation of distinct STATs and expression of Th subset fate-determining master regulatory genes. Stimulation with A27 recruited TRAF-1 and -2, activated STAT-1, -4 and JNK1/2, and induced transcription factor T-bet. On the other hand, activation with A35 recruited TRAF-6, activated STAT-3 and p38 MAPK, and induced RORγt. In contrast, A41 recruited TRAF-3 and -5, activated STAT-5, -6 and ERK1/2, and produced GATA-3. Remarkably, A27 induced the conversion of CD25+Foxp3+ Treg cells to IFN-γ-producing Th1 cells with a concomitant suppression of Foxp3 and TGF-β expression both in healthy individuals as well as cancer patients. A35 also, but not A41, suppressed the expression of Foxp3 and induced IL-17 in Treg cells. A27 alone, but not others produced a strong anti-tumor effect in a human tumor xenograft model of humanized mice in an IFN-γ- and Treg conversion-dependent mechanism. Taken together, the data that AITR regulates Th subset polarization and eradicates solid tumors can be a target for broad-spectrum immune check point therapeutics against cancers and autoimmune diseases.
Citation Format: Byoung S. Kwon, Seung J. Lee, Young H. Kim, Joong W. Lee, Sun H. Hwang, Dass S. Vinay. Activation-inducible TNFR family receptor (AITR) signaling mediates the polarization of CD4+ T cells into Th1, Th2, and Th17, converts Treg to Teff and eradicates solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3235.
Abstract 3237: Combinatorial immune checkpoint inhibitor therapy in anaplastic thyroid cancer
Authors: Chakraborty Sanjukta , Maniyar Rachana R. , Dadafarin Sina , Rahoma Ghada Ben , Singh Sarnath , Moscatello Augustine , Geliebter Jan , Tiwari Raj K. 
Published: August 2019

Abstract
Anaplastic thyroid cancer(ATC) is a rare but extremely aggressive form of endocrine malignancy that accounts for only 1-2% of total thyroid cancer cases but responsible for 20-30% of annual mortality from thyroid cancer in the USA. Genetic lesion landscape in ATC is not conducive to multiple targeted therapies. BRAF mutation is one of the dominant genetic lesions observed in 30-40% of ATC cases and 98% of them are BRAFV600E positive. Due to the limited therapeutic efficacy of BRAFV600E inhibitor vemurafenib, identification of novel therapeutic candidates would provide a viable alternative. Immunecheckpoint therapies have showed huge promise in recent years but are relatively underexplored in ATC patients. To this end, 4 ATC cell lines 8505C, T238, SW1736 and HTh74; 3 PTC cell lines TPC-1, BCPAP and K1 and 1 FTC cell line CGTH-W-1 were screened for expression of 29 immune-checkpoint molecules by qRT PCR with or without 10μM vemurafenib treatment for 24 hrs. Initial screening revealed a differential expression level of the transcripts among the cells. Vemurafenib treatment further up regulated expression of CD160, HVEM, BTLA, TIM3 and galectin9 in cell lines positive for BRAFV600E mutation (8505C, SW1736, BCPAP) and the ones harboring an additional PIK3CA mutation (T238, K1). This observation was further confirmed by immunocytochemistry. CD160 was not detected in any of the cell lines except for K1, TPC-1 and NTHY at protein level. Flow cytometry confirmed presence of BTLA, HVEM and TIM3 on the surface of these tumor cells which would enable them to engage their cognate ligands on T cells and suppress antitumor immune response. Western blots confirmed upregulation of BTLA, HVEM, TIM3 and galectin 9 in response to vemurafenib in both BRAFV600E positive cell lines and HTh74. Expression of these molecules were also validated by immunohistochemistry in patient samples. In an effort to evaluate the functional activity of these immunecheckpoint molecules, co-culture studies were done. Both HVEM and BTLA showed immunomodulatory capability and were capable of redirecting T cell differentiation towards a suppressive phenotype. Preclinical studies with combination of BRAFV600E or PI3K inhibitor and antagonistic antibodies against these molecules are currently underway. This study has identified two novel immune checkpoint molecules in ATC and might provide viable therapeutic targets.
Citation Format: Sanjukta Chakraborty, Rachana R. Maniyar, Sina Dadafarin, Ghada Ben Rahoma, Sarnath Singh, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari. Combinatorial immune checkpoint inhibitor therapy in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3237.
Abstract 3246: Dynamics of T-cell checkpoint receptor profiles during melanoma progression
Authors: Edwards Jarem , Tasker Annie , Silva Inês Pires da , Quek Camelia , Allanson Benjamin M. , Saw Robyn P. M , Thompson John F. , Menzies Alexander M. , Palendira Umaimainthan , Wilmott James S. , Long Georgina V. , Scolyer Richard 
Published: August 2019

Abstract
Background A myriad of novel monoclonal antibody based immunotherapies targeting co-stimulating and co-inhibitory receptors have entered clinical trials in melanoma with the aim of increasing response rates and overcoming resistance to standard anti-CTLA-4 and anti-PD-1 immunotherapy. However, little is known about the abundance, co-expression and immune cells enriched for each specific drug target in the various stages of melanoma progression. Therefore, we sought to assess the relative abundance of checkpoint receptors and their expression during melanoma disease progression, as well as the immune cells enriched for each of these molecules.
Methods - Multiplex immunofluorescence staining for immune checkpoint receptors (ICOS, GITR, OX40, PD-1, TIM-3, and VISTA) was performed on 95 melanoma biopsies from 41 melanoma patients, including patient matched biopsies for primary, regional lymph node or distant metastases. - Mass cytometry was performed on leukocytes isolated from 18 treatment-naïve melanoma tumors to explore immune subsets enriched for many of the checkpoint receptors currently targeted in clinical trials.
Results & Conclusions GITR and OX40 were the least abundant checkpoint receptors in melanoma (p&lt;0.001), with less than 1% of intra-tumoral T cells expressing either marker. TIM-3 and VISTA were mostly expressed on non-T cell populations, with TIM-3 enriched on dendritic cells. Tissue resident T cells (CD69+ CD103+ CD8+) represented a population highly enriched for TIGIT (&gt;70%) and other co-inhibitory receptors but not co-stimulatory receptors. The proportion of GITR+ T cells decreases from primary melanoma (&gt;5%) to patient matched lymph node (&lt;1%, p=0.04) and distant metastases (&lt;1%, p=0.0005). This data will underpin future clinical trial design and provide a rationale for combining these molecules in the clinic.
Note: This abstract was not presented at the meeting.
Citation Format: Jarem Edwards, Annie Tasker, Inês Pires da Silva, Camelia Quek, Benjamin M. Allanson, Robyn P. M Saw, John F. Thompson, Alexander M. Menzies, Umaimainthan Palendira, James S. Wilmott, Georgina V. Long, Richard Scolyer. Dynamics of T-cell checkpoint receptor profiles during melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3246.
Abstract 326: Enhanced efficacy of Sitravatinib (MGCD516) in metastatic models of antiangiogenic therapy resistance
Authors: Dolan Melissa , Mastri Michalis , Tracz Amanda , Christensen James G. , Chatta Gurkamal , Shi Yuhao , Ebos John M. 
Published: August 2019

Abstract
Tyrosine kinase inhibitors (TKIs) that primarily target vascular endothelial growth factor receptors (VEGFRs) are approved to treat several cancers in the metastatic setting. However, improvements in survival for most patients are short-lived and resistance is common. Sequential treatment or ‘switching’ from one VEGFR TKI to another has proven effective following failure in many instances. This may be due to broad drug-specific secondary TKI target profiles that can block metastasis- and angiogenesis-promoting processes. Here we examined sitravatinib (MGDC516), a novel small molecule TKI with activity against VEGFRs, that also can block Met, Axl, and several ephrin receptors (Eph), amongst several others. Transcriptomic and proteomic analysis showed multiple sitravatinib targets upregulated in VEGFR TKI-resistant mouse and human tumor cell lines derived from metastasis in mice. In vitro, sitravatinib treatment decreased proliferation in VEGFR TKI-resistant cells compared to untreated controls, suggesting prior RTKI resistance may enhance sitravatinib anti-tumor potency, while cabozantinib, a multi-targeted RTKI clinically approved after antiangiogenic therapy failure did not demonstrate enhanced anti-proliferative activity in resistant cells. In vivo, sitravatinib treatment significantly reduced orthotopically-implanted primary kidney and breast tumors in mice, with increased effects observed in VEGFR TKI-resistant tumors. Sitravatinib treatment was also found to suppress metastatic disease progression and improve survival in mice when continued after primary tumor removal, indicating metastasis-inhibiting effects of sitravatinib may be enhanced in VEGFR TKI-resistant settings. Together, these studies suggest that broad-spectrum RTKI inhibitors such as sitravatinib that target multiple metastasis-promoting mechanisms improve efficacy after antiangiogenic treatment failure and improve outcomes in a second-line setting.
Citation Format: Melissa Dolan, Michalis Mastri, Amanda Tracz, James G. Christensen, Gurkamal Chatta, Yuhao Shi, John M. Ebos. Enhanced efficacy of Sitravatinib (MGCD516) in metastatic models of antiangiogenic therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 326.
Abstract 328: ADAM17-induced activation of HER receptors mediate resistance to trastuzumab in a subset of moderate HER2-expressing breast cancer cells
Authors: Feldinger Katharina , Vigneswara Vasanthy , Murphy Gillian , Kong Anthony 
Published: August 2019

Abstract
Currently anti-HER2 therapies are indicated for HER2-positive breast cancer patients that are IHC3+ or FISH positive. However, there have been studies suggesting that some HER2-negative patients may also respond to these treatments. Previously, our laboratory showed that trastuzumab upregulates ADAM17 and ADAM10 levels; and the resultant ligand release and the activation of HER receptors mediates trastuzumab acquired resistance in HER2-positive breast cancer. The aim of this study is to further understand the mechanisms of response and resistance of HER2 targeting agents such as trastuzumab and neratinib in low and moderate HER2-expressing breast cancer cells.
The HER2 expression of a panel of eight breast cell lines was assessed by IHC, FISH, western blot, and qRT-PCR. Using cell viability studies we found that in comparison with high (IHC 3+) and low HER2 expressing (IHC 0 or 1+) breast cancer cells, moderately expressing HER2 (2+) cells showed an intermediate response to trastuzumab and neratinib. Three moderate HER2-expressing breast cancer cell lines (IHC 2+), MDA-MB-361, MDA-MB-453 and HCC1569 were shown to respond to increasing doses of neratinib (with an IC50 less than 30nM). However, increasing doses of trastuzumab (up to 120 μg/ml) was unable to decrease the cell viability of these cells to below 50% of the control. The response to trastuzumab and neratinib correlated with basal ADAM17 but not ADAM10 expression. Trastuzumab treatment led to an upregulation of ADAM17 and the shedding of HER ligands in the media, as well as the phosphorylation of HER members. ADAM17 inhibition, using a specific anti-ADAM17 antibody or knockdown of the protein, decreased activation of HER members as well as downstream markers, correlating with reduced cell viability in moderate HER2-expressing cell lines. In addition, the combination of trastuzumab with neratinib was more effective than either single agent in moderate HER2-expressing cell lines.
Thus, ADAM17 may play a key role in the resistance to trastuzumab in moderate HER2-expressing breast cancer cells. Combining trastuzumab with an ADAM17 inhibitor or an irreversible pan-HER inhibitor such as neratinib may be an effective therapeutic strategy for targeting breast cancers with moderate HER2 expressing tumors.
Citation Format: Katharina Feldinger, Vasanthy Vigneswara, Gillian Murphy, Anthony Kong. ADAM17-induced activation of HER receptors mediate resistance to trastuzumab in a subset of moderate HER2-expressing breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 328.
Abstract 3280: TTFields induces immunogenic cell death and STING pathway activation through cytoplasmic double-stranded DNA in glioblastoma cells
Authors: Chen Dongjiang , Thomas Nagheme , Tran David D. 
Published: August 2019

Abstract
Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggressive chemoradiotherapy. Tumor Treating Fields (TTFields) was recently approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM patients. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly, leading to disrupted chromosomal segregation, integrity and stability. In many patients, a transient stage of increased peritumoral edema is often observed early in the course of TTFields treatment followed subsequently by objective radiographic responses, suggesting that a major component of therapeutic efficacy by TTFields may be an immune mediated process. However, the mechanism underlying these observations remains unclear. Here we report results on a panel of GBM cell lines treated with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system. Our data showed 24 hrs TTFields-treated GBM cells had a significantly higher rate (19.9% vs. 4.3%, p=0.0032) of micronuclei structures released into the cytoplasm as a result of TTFields-induced chromosomal instability. Nearly 40% of these micronuclei were co-localized with two upstream dsDNA sensors: absent in melanoma 2 (AIM2)andInterferon (IFN)-inducible proteinCyclic GMP-AMP synthase (cGAS), compared to absence of co-localization in untreated cells. TTFields-activated micronuclei-dsDNA sensor complexes led to i) induction of pyroptotic cell death, as measured by a specific LDH release assay, and through AIM2-recruited caspase1 and cleavage of pyroptosis-specific Gasdermin D; and ii) activation of STING pathway components including Type I IFNs and pro-inflammatory cytokines downstream of the NFκB pathway. GBM cell-specific shRNA depletion of either AIM2 or STING or both in a co-culture experiment of bone marrow cells or splenocytes with supernanants obtained from knockdown GBM cells was able to reverse the inducement of immune cells. These results provide compelling evidence that TTFields function as an activator of the immune system in GBM cells, and a strong rationale for combining TTFields with immunotherapy aimed at augmenting an anti-tumor immune response such as immune checkpoint inhibitors.
Note: This abstract was not presented at the meeting.
Citation Format: Dongjiang Chen, Nagheme Thomas, David D. Tran. TTFields induces immunogenic cell death and STING pathway activation through cytoplasmic double-stranded DNA in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3280.
Abstract 3287: Survival disparities for second primary malignancies diagnosed among childhood cancer survivors: A population-based assessment
Authors: Brown Austin L. , Arroyo Vidal M. , Agrusa Jennifer , Scheurer Michael E. , Gramatges Maria M. , Lupo Philip J. 
Published: August 2019

Abstract
Background: Curative therapy places childhood cancer survivors at increased risk of second primary malignancies (SPMs). However, there have been few population-based attempts to characterize differences in outcomes between SPMs in childhood cancer survivors and comparable de novo first primary malignancies (FPMs).
Methods: We extracted clinical and demographic information from childhood cancer survivors who developed SPMs and from individuals with comparable de novo FPMs using the Surveillance, Epidemiology, and End Results (SEER) 1973-2015 database. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated with Cox proportional hazards models comparing overall survival (OS) between individuals with and without a history of childhood cancer. OS was evaluated overall and within specific cancers diagnosed in ≥50 childhood cancer survivors. Models accounted for potential confounders, including sex, race, age, decade of diagnosis, histology, and disease stage.
Results: Compared to individuals with FPMs (n=1,332,203), childhood cancer survivor with a similar SPM as the FPMs (n=1,409) experienced poorer OS (HR=1.86, 95%CI: 1.72-2.02) after accounting for age, sex, race, and decade of diagnosis. Estimated five-year overall survival for SPMs diagnosed in survivors of childhood cancer was 61.7% (95% CI: 58.9-64.4), compared to 77.4% (95% CI: 75.0-79.5) among de novo FPMs propensity score-matched on confounding factors. A history of childhood cancer remained a poor prognostic factor for all specific cancer evaluated, including: breast (HR=2.07, 95%CI: 1.63-2.62), thyroid (HR=3.59, 95%CI: 2.08-6.19), acute myeloid leukemia (HR=2.38, 95%CI:1.87-3.05), brain (HR=2.09, 95%CI:1.72-2.55), melanoma (HR=2.57, 95%CI: 1.55-4.27), bone (HR=1.88, 95%CI:1.37-2.57), and soft tissue sarcoma (HR=2.44, 95%CI: 1.78-3.33). Survival disparities were most pronounced in survivors diagnosed with a childhood cancer before age 10 (HR=2.83, 95%CI: 2.46-3.25), diagnosed with a SPM within 10 years of the childhood cancer (HR=2.61, 95%CI: 2.29-2.99), and exposed to radiotherapy during childhood (HR=2.13, 95%CI: 1.92-2.37).
Conclusion: Compared to individuals without a prior cancer diagnosis, survivors of childhood cancer with a SPM experience inferior outcomes. These survival disparities persist across cancer types, therapeutic exposures, and clinical factors.
Citation Format: Austin L. Brown, Vidal M. Arroyo, Jennifer Agrusa, Michael E. Scheurer, Maria M. Gramatges, Philip J. Lupo. Survival disparities for second primary malignancies diagnosed among childhood cancer survivors: A population-based assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3287.