bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4124: Expressions of co-inhibitory / co-stimulatory molecules may impact immune checkpoint therapies
Authors: Daftarian Pirouz M. , George Marybeth , Kleiman Eden , Ouerkaxi Wushouer , Yamamura Amy , Li Zhongliang , Zang Mingfa , Yu Derron , Hwang Eunmi , An Annie X. , Lin Ann E. , Li Henry 
Published: August 2019

Abstract
Screening patient peripheral blood using our proposed non-invasive method can boost the accuracy in selecting proper candidates for immune checkpoint therapy in the clinical setting, thereby leading to higher success in treatment. The immune system is regulated by a sophisticated network of modulatory molecules. In chronic infections and cancers, T cell exhaustion can arise when clearance of antigens is incomplete due to sustained expression of co-inhibitory molecules. T cell exhaustion has been exploited by some cancers, and also described in chronic infections with latency. Such exhausted T cells may be reversed with the right immune checkpoint blockade, thereby restoring effector T cell function. We have optimized a T cell Exhaustion Recall Antigen Assay, demonstrating T cell exhaustion may be reversed by immune checkpoint blockades in certain hosts. We hypothesize that understanding of the capacity and expressions of co-inhibitory molecules assist in predicting responders for specific immune checkpoint therapies. We have used a flow cytometry-based approach to examine changes in an array of immune checkpoint molecules on activated T cells and antigen presenting cells. We first tested the effect of anti-PD1 on tumor antigen-specific activated T cells using splenocytes from PMEL T cell receptor (TCR) transgenic mouse, which expresses mouse homologue of human premelanosome protein, or gp100. Activated CD3+CD8+ gp100-specific T cell population and IFNγ production were measured by flow cytometry. Secondly, we evaluated the expression levels of various immune checkpoint molecules post anti-CD3 stimulation of human peripheral blood mononuclear cells (PBMC) from characterized healthy hosts. Surprisingly, we found high expressions of co-inhibitory and co-stimulatory molecules including CTLA-4, PD1, PDL-1/PDL2, TIGIT, LAG3, TIM3, GITR, are associated with poor response to immune checkpoint blockades. Levels of activated T cells and cytokine production in donors with high checkpoint receptors showed lower T cell activations and cytokine production. Screening patient peripheral blood using our proposed non-invasive method can boost the accuracy in selecting proper candidates for immune checkpoint therapy in the clinical setting, thereby leading to higher success in treatment.
Citation Format: Pirouz M. Daftarian, Marybeth George, Eden Kleiman, Wushouer Ouerkaxi, Amy Yamamura, Zhongliang Li, Mingfa Zang, Derron Yu, Eunmi Hwang, Annie X. An, Ann E. Lin, Henry Li. Expressions of co-inhibitory / co-stimulatory molecules may impact immune checkpoint therapies [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 4124.
Abstract 4125: Precise and reproducible measurement of tumor mutational burden using panel sequencing: the role of panel size and of mutation types
Authors: Budczies Jan , Rempel Eugen , Allgäuer Michael , Kazdal Daniel , Endris Volker , Schirmacher Peter , Stenzinger Albrecht 
Published: August 2019

Abstract
Tumor mutational burden (TMB) is an emerging biomarker for patient stratification for immune checkpoint inhibition. Implementing TMB measurement by panel sequencing, experimental setup and bioinformatics pipelines need to be optimized to minimize sources of error and variance. To gain insight into contributors to TMB variance, combinatorial calculations were performed based on the hypothesis that each base in the coding sequence was mutated with the same probability. Simulations of sequencing panels in the TCGA data were performed to check for additional contributors to the variance. A narrow definition of TMB including only missense mutations was compared to a broader definition additionally including other mutation types. The quantity under investigation was TMB measured in relatively to the size of the panel (per Mbp). The combinatorial contribution to the coefficient of variation (CV) of TMB turned out to be inversely proportional to the square root of the panel size and inversely proportional to the square root of the TMB. For a tumor with TMB of 10 muts/Mbp, the combinatorial CV increased drastically for panels sizes smaller than 1.5 Mbp. The combinatorial variance represents a persistent contribution to the error of TMB calculation that cannot be avoided. Simulations in WES data confirmed the combinatorial variance as main contributor to the imprecision of TMB estimation. In many instances, the fold change between the number of all mutations in the coding sequence and the number of missense mutations was similar for tumors of the same cancer type. However, the fold changes were different in specific cancer types for example significantly higher in melanoma (1.66) compared lung adenocarcinoma (1.48). In particular, the former tumors were observed to include a higher proportion of synonymous mutations than the latter. The combinatorial source of error implies that a panel of least 1.5 Mbp is needed to precisely determine TMB for tumors ranging around typical currently used diagnostic thresholds (10 muts/Mbp). Additional sources of error might even favor larger panel sizes such as 3 Mbp. The combinatorial error can be reduced by including all mutations types instead of only missense mutations and simultaneously adjusting TMB with a cancer type specific factor.
Citation Format: Jan Budczies, Eugen Rempel, Michael Allgäuer, Daniel Kazdal, Volker Endris, Peter Schirmacher, Albrecht Stenzinger. Precise and reproducible measurement of tumor mutational burden using panel sequencing: the role of panel size and of mutation types [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 4125.
Abstract 4133: The in vitro melanoma tumor microenvironment conditions macrophages to an immunosuppressive M2-like phenotype, which is reversible by oncolytic virus ORCA-010 with immune modulators
Authors: Milenova Ioanna E. , Ven Rieneke van de , Dong Wenliang , Beusechem Victor W. van , Gruijl Tanja D. de 
Published: August 2019

Abstract
The melanoma tumor environment suppresses the immune reaction, favoring tumor escape from the immune system. This suppressive environment is in part sustained by tumor associated M2-like macrophages. In order to activate the immune system, one approach is macrophage-targeted therapies, that repolarize M2-like macrophages to M1-like macrophages. ORCA-010 is a potency enhanced, replication selective oncolytic adenovirus, with strong anti-tumor activity.
As a model of macrophage polarization in the tumor microenvironment, human melanoma cell lines were co-cultured in vitro with CD14+ monocytes. The effects to induce M1-like macrophages by addition of lipopolysaccharide (LPS) and interferon (IFN)-gamma, JAK2 or p38 MAPK inhibitors combined with ORCA-010, was assessed in the co-cultures. Cell phenotypes were characterized by flow cytometry.
Our data demonstrate that ORCA-010 significantly reduces M2-like macrophage marker CD163 on CD45+ cells in co-cultures, and increases co-stimulatory M1-like macrophage markers CD80 and CD86 expression on macrophages. CD80 is significantly up-regulated by ORCA-010 with LPS and IFN-gamma. Next, the macrophage polarizing effects of combining ORCA-010 with p38 MAPK and JAK2 inhibitors, known for their favorable myeloid M1 and dendritic cell skewing properties, were assessed in the melanoma co-cultures. The inhibitors JAK2 (AG490) and p38 MAPK (LY2228820) both significantly reduced CD163 levels, however did not induce increased CD80 and CD86 by themselves. Only when combining these with ORCA-010 did we observe a CD86 up-regulation.
In a B16.OVA immunocompetent mouse model, ORCA-010 appeared to enhance recruitment of CD8+ T cells to the tumor. Interestingly, combining ORCA-010 with anti-PD-1 resulted in a significant increase of recruitment of CD8+ T cells at the tumor, which could be further enhanced by co-treatment with a p38 inhibitor.
Our data suggest that ORCA-010 induces a repolarization of the M2-like macrophages to a favorable M1-like phenotype. This can be further enhanced by the combined administration of ORCA-010 with a TLR4 agonist and IFNγ, or with a JAK2 inhibitor.
This work is supported by the European Union Horizon2020 ITN-EID grant 643130 “VIRION”.
Citation Format: Ioanna E. Milenova, Rieneke van de Ven, Wenliang Dong, Victor W. van Beusechem, Tanja D. de Gruijl. The in vitro melanoma tumor microenvironment conditions macrophages to an immunosuppressive M2-like phenotype, which is reversible by oncolytic virus ORCA-010 with immune modulators [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 4133.
Abstract 4141: The induction of iNKT cells and CIK cells toward anti-tumor phenotypes
Authors: Wongkajornsilp Adisak , Htwe Khin Su Su , Sawatpiboon Nathawadee , Duangsa-ard Sunisa , Kasetsinsombat Kanda 
Published: August 2019

Abstract
Natural killer T (NKT) cells and cytokine-induced killer (CIK) cells contain features of both T cells and NK cells that occasionally brought confusion to several studies. These cells have been reported to possess either anti-tumor or immunosuppressive properties. NKT cells could be directly isolated from the peripheral blood, while CIK cells require ex vivo culture of peripheral blood lymphocytes for 2-3 weeks with IFN-γ, IL2 and anti-CD3. NKT type I cells carry invariant TCRαβ recognizing α-Galcer loaded CD1d on antigen-presenting cells. We investigated whether NKT type I cells, as well as CIK cells, could be induced toward Th1 phenotype that should elicit anti-tumor activity. The inducers included ODN, checkpoint inhibitors and CDKi. We observed the tipping toward Th1 phenotype in both cell types, especially on CIK cells. It is concluded that both NKT type I cells and CIK cells could be induced toward the anti-tumor Th1 phenotype.
Citation Format: Adisak Wongkajornsilp, Khin Su Su Htwe, Nathawadee Sawatpiboon, Sunisa Duangsa-ard, Kanda Kasetsinsombat. The induction of iNKT cells and CIK cells toward anti-tumor phenotypes [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 4141.
Abstract 4151: Siglec-15 is a novel immunomodulatory effector of adaptive immune evasion in acute lymphoblastic leukemia
Authors: Pillsbury Claire , Fonseca Jairo A. , Dougan Jodi , Gardner Lori , Rabe Jennifer , Gearheart Christy , Porter Chris C. 
Published: August 2019

Abstract
Despite advances in therapy for acute lymphoblastic leukemia (ALL), it remains a leading cause of illness-related death in children and has poor long term disease-free survival and prognosis in recurrence in adults. Recent developments in immune-based therapies, such as CAR T cells, have shown great promise, but immune evasion mechanisms of leukemia remain poorly understood, and alternative strategies to engage the immune system are needed.
Our group has characterized a role for calcineurin (CN) as a driver of a potent immune escape mechanism in an aggressive murine model of BCR-ABL+ ALL. We performed RNA-seq analysis of control and CN-deficient ALL cells to identify downstream mediators of this effect. Siglec-15 emerged as one of the most differentially expressed genes, being preferentially downregulated in the more immunogenic CN-deficient cells. The role of this Siglec-family immunomodulator is yet unstudied in the context of leukemia and could represent a novel mechanism for immune evasion.
We first validated lower expression of Siglec-15 in CN-deficient leukemia cells by RT-qPCR. We next mined publicly available databases, which revealed higher expression of Siglec-15 in primary B-ALL and AML leukemias as compared to normal PBMCs, as well as in post-chemotherapy MRD samples as compared to at-diagnosis samples. Western blot analysis of human leukemia cell lines demonstrated upregulation of Siglec-15 expression in B-ALL, some AML, as well as DLBCL, as compared to normal PBMCs.
To determine if Siglec-15 mediates immune evasion in vivo, we knocked down Siglec-15 in the murine model of BCR-ABL+ ALL, which resulted in rapid suppression of the leukemia following engraftment in immunocompetent mice, an effect lost in immunocompromised counterparts. Preliminary studies with cells in which Siglec-15 was knocked-out using CRISPR/Cas9 revealed similar results. Importantly, Siglec-15-deficient cells do not have any changes in proliferation or susceptibility to DNA damage-induced apoptosis.
To address the capacity for therapeutic targeting of Siglec-15, mice with parental leukemia were treated with a monoclonal blocking antibody against Siglec-15, yielding an overall reduction in leukemic burden and prolonged survival. Taken together, these results suggest that Siglec-15 is a novel immunomodulatory effector and has a therapeutically exploitable role in immune evasion of ALL.
Citation Format: Claire Pillsbury, Jairo A. Fonseca, Jodi Dougan, Lori Gardner, Jennifer Rabe, Christy Gearheart, Chris C. Porter. Siglec-15 is a novel immunomodulatory effector of adaptive immune evasion in acute lymphoblastic leukemia [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 4151.
Abstract 4152: Irreversible electroporation induces immunogenic cell death and mediates durable response in orthotopic PDAC model in combination with anti-PD-1
Authors: Zhao Jun , Wen Xiaofei , Li Tingting , Melancon Marites , Gupta Sanjay , Peng Weiyi , Li Chun 
Published: August 2019

Abstract
Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) because of the presence of an immunosuppressive tumor-associated stroma. Here, we showed that combined IRE and anti-PD-1 immune checkpoint blockade significantly suppressed tumor growth and prolonged the lives of immunocompetent mice bearing well-established orthotopic PDAC. Remarkably, more than 35% of mice had a durable response, and were found to be free of residual tumor upon necropsy. All mice that survived for 60 days after IRE and anti-PD1 treatments rejected tumor cell re-challenge. Analyses of splenocytes confirmed that these long-term survivors developed an anti-tumor memory T cell response. Further mechanistic studies unveiled that the efficacy of IRE + anti-PD-1 could be attributed to multiple factors, including rapid release of danger associated molecular patterns, activation of DCs, and alleviation of immunosuppressive tumor microenvironment. Neutralization of CD8+ T cells by anti-CD8 antibody nullified the antitumor effect of combined IRE and anti-PD-1, suggesting that tumor-infiltrating CD8+ T cells played a key role in mediating the anti-tumor efficacy of IRE + anti-PD-1.Given that both IRE and anti-PD-1 antibodies are already used in the clinic, our results support the translation of this combination as a promising approach for treating patients with PDAC.
Citation Format: Jun Zhao, Xiaofei Wen, Tingting Li, Marites Melancon, Sanjay Gupta, Weiyi Peng, Chun Li. Irreversible electroporation induces immunogenic cell death and mediates durable response in orthotopic PDAC model in combination with anti-PD-1 [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 4152.
Abstract 4156: Multiple rare germline variants in a thyroid cancer family
Authors: Nieminen Taina T. , Comiskey Daniel F. , Wang Yanqiang , Liyanarachchi Sandya , Brock Pamela , Peltomaki Paivi , He Huiling , Chapelle Albert de la 
Published: August 2019

Abstract
Thyroid cancer is the 12th most common cancer in the USA. Four main types exist: the majority (85-90%) is papillary thyroid cancer (PTC). Familial form of PTC represents 5 to 15 % of all thyroid cancers. We have access to 155 PTC families including clinical data and biological samples. Our aim was to search for highly penetrant gene variants in 17 PTC families. Data from one of the families in which PTC is segregating in three generations are described here. Whole genome sequencing was performed in three family members affected by PTC. Sanger sequencing at germline DNA and RNA levels followed by TOPO cloning was used to study the effects of mutations. We found 4 different either novel or ultra-rare mutations in the ITGAD, AARS and PDPR genes on chromosome 16 (Table). All mutations segregated perfectly with PTC in family members (n=4) and were absent in unaffected members (n=3). We Sanger sequenced cDNA from two of the PTC patients and cloned the products into the pCR 2.1-® TOPO vector. Based on the cDNA sequencing and cloning results, all of the mutations will create a premature stop codon leading to a truncated protein. We will verify the effects of the mutations by protein analysis as well. In addition, structural variation analysis will be done to exclude large genomic rearrangements. The germline events leading to PTC are neither well known nor extensively researched. When occurring in families PTC regularly shows autosomal dominant inheritance with incomplete penetrance. Only a few of probable mutations have been reported. Nevertheless, our finding of the truncating mutations in 3 genes on chromosome 16 that are cosegregating with PTC in a 3-generation family is surprising. Even more so: is the localization of the three genes in one chromosome coincidental? Preliminary findings in some of the other 16 PTC families suggest that the occurrence of more than one truncating mutation is not a unique event. We look forward to answer the question whether combination of two or more mutant genes can be responsible for one disease segregating in families.
Citation Format: Taina T. Nieminen, Daniel F. Comiskey, Yanqiang Wang, Sandya Liyanarachchi, Pamela Brock, Paivi Peltomaki, Huiling He, Albert de la Chapelle. Multiple rare germline variants in a thyroid cancer family [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 4156.
Abstract 4164: Comprehensive analysis of germline variants in patients with hereditary breast and ovarian cancer susceptibility from 4 countries of Latin America
Authors: Vaca-Paniagua Felipe , Quezada-Urban Rosalia , Velásquez Clara Estela Díaz , García Eva María Gómez , Catalá Claudia Fabiola Méndez , Oliver Javier , Franco Alejandra , Frecha Cecilia , Riggi Cecilia , Carranza Claudia , Altamirano Carlos Castañeda , Gómez Ana Milena , Montealegre Ana Lorena , Chaparro Sandra Gaitán , López Juan Javier , Perdomo Sandra 
Published: August 2019

Abstract
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant disease mainly associated to high-risk pathogenic alleles in the BRCA1 and BRCA2 genes, but only in ~25% of HBOC cases. With the emergence of broader multi-gene panels, population-based studies have revealed that 3-4% of high-risk individuals have germline pathogenic variants in cancer risk genes other than BRCA1 and BRCA2, including ATM, CHEK2, PALB2, PTEN, TP53, and others. One of the understudied population with HBOC is the Latin American, and in this study, we aimed to identify the prevalence of high, moderate and new pathogenic alleles within two panels of cancer predisposition genes (143 and 86 genes) in 217 Latino breast cancer patients that met the NCCN criteria for panel testing in 4 countries. The Latino population was integrated by 68 Mexicans (31.3%), 19 Guatemalan (8.8%), 56 Argentinians (25.8%) and 74 Colombians (34.1%). We detected (i) 19.4% patients with pathogenic variants (42/217; Mexicans: 12, 5.5%; Guatemalans: 3, 1.4%; Argentinians: 10, 4.6%; Colombians: 17, 7.8%); (ii) 36.9% harbored variants with unknown clinical significance (VUS) (80/217; Mexicans: 24, 11.1%; Guatemalans: 6, 2.7%; Argentines: 26, 12%; Colombians: 24, 11.1%) and (iii) 43.7% were negative (95/217; Mexicans: 32, 14.7%; Guatemalans: 10, 4.6%; Argentines: 20, 9.2%; Colombians: 33, 15.2%). Moreover, most of the pathogenic variants (66%, 28/42) were found in high-risk genes including BRCA1/2, MSH2, MSH6 and PALB2. Our findings show the high locus heterogeneity of HBOC in the Latin American population. To establish the level of risk and the ultimate clinical utility of the variants detected in expanded panels tests, further international efforts are necessary in a population-based context.
Citation Format: Felipe Vaca-Paniagua, Rosalia Quezada-Urban, Clara Estela Díaz Velásquez, Eva María Gómez García, Claudia Fabiola Méndez Catalá, Javier Oliver, Alejandra Franco, Cecilia Frecha, Cecilia Riggi, Claudia Carranza, Carlos Castañeda Altamirano, Ana Milena Gómez, Ana Lorena Montealegre, Sandra Gaitán Chaparro, Juan Javier López, Sandra Perdomo. Comprehensive analysis of germline variants in patients with hereditary breast and ovarian cancer susceptibility from 4 countries of Latin America [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 4164.
Abstract 4165: Unstable microsatellite instability proportion among unselected ovarian and endometrial cancer patients among Korean population
Authors: Kim Min Kyu 
Published: August 2019

Abstract
Background: There are several availability of microsatellite instability(MSI) among ovarian and endometrial cancer for detection of Lynch syndrome and biomarker of immune chemotherapeutic treatment. We investigated to know proportion of abnormal microsatellite instability (MSI-L/H).
Methods: Through retrospective search,we identified 51 cases of MSI samples from ovary and endometrial cancer visiting hereditary gynecologic cancer center.
Results: We found 34 ovary cancer, 13 endometrial cancer and 4 colon cancer patients. Median age was 56.6(18~78). About thirty percent have family cancer history among patient relatives (14/45(31.1%)). Early stage cancer (I~II) (4/25,16.0%) have higher incidence than late stage cancer (III~IV) (2/28,7.1%). Abnormal MSI have three serous type and endometrioid type pathology. Among abnormal MSI, we found two MSI-L and four MSI-H (6/51(11.8%)). We found one MSI-H ovary cancer,3 MSI-H endometrial cancer patients (1/34(2.9%),3/13(23.1%)).
Conclusions: There are about 10 percent of abnormal MSI in this study group
Citation Format: Min Kyu Kim. Unstable microsatellite instability proportion among unselected ovarian and endometrial cancer patients among Korean population [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 4165.