bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A158: Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments
Authors: Tavernier Jan H. 
Published: February 2019

Abstract
An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I interferon (IFN), for instance, has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its optimal clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1000-fold more potent on targeT-cells, allowing specific signaling in selected cell types only. As conventional dendritic cells (cDC) are essential for IFN antitumor efficacy, we targeted type I IFN-derived “AcTaferon (AFN)” to Clec9A+ cDC. Clec9A-AFN therapy displayed strong antitumor activity in murine melanoma (B16), breast carcinoma (4T1) and lymphoma models (A20), as well as against human RL lymphoma in immunodeficient NSG mice reconstituted with a human immune system. In sharp contrast to wild-type IFN therapy, the antitumor efficacy of Clec9A-AFN was not accompanied by any detectable toxicity, assessed by body weight and several hematologic parameters. Clec9A-AFN effects were lost in CD8-depleted or Batf3-/- mice, and depended on IFN signaling in cDCs but not in T lymphocytes. Combined with anti-PDL1 immune checkpoint blockade, Treg-depleting anti-CTLA4 + anti-OX40 therapy, immunogenic chemotherapy, or low-dose TNF, complete tumor regressions and long-lasting tumor immunity (memory) were obtained, still without any adverse effects. Our findings thus indicate that DC-targeted AFN provides a highly efficient, off-the-shelf and safe cancer immunotherapy, with possible application in a broad range of malignancies.
Citation Format: Jan H. Tavernier. Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A158.
Abstract A160: Deep immunoprofiling of mouse lung cancer models in steady state and upon drug treatment.
Authors: Maldegem Febe van , Valand Karishma , Tsang Victoria , Mugarza Edurne , Caswell Deborah , Hobson Philip , Downward Julian 
Published: February 2019

Abstract
With the advancement of immunotherapies for lung cancer, it has become apparent how insufficient our knowledge is surrounding the interactions between the tumor and the immune system. In particular in the context of combining immunotherapy with conventional chemotherapy or novel targeted therapies, it is of the utmost importance that we understand the effects that those therapies have on the tumor immune infiltrate and how that would counteract or synergize with immunotherapy. We have used multiplex flow cytometry to characterise the basal tumor immune infiltrate of various spontaneous and orthogonous syngeneic mouse models for lung cancer, with different levels of immunogenicity. With imaging mass cytometry, visualizing and quantifying &gt;30 markers simultaneously in mouse tumor tissue sections, we studied the localization and interactions of the immune cells within and surrounding the tumors. This has highlighted the level to which tumors are regulating their microenvironment, actively excluding all potential effector cells while attracting protumoral myeloid cells, and how this is amplified as the tumors progress. We have observed differences between the various models and seen how the tumors make adaptations when they are intrinsically more immunogenic. Furthermore, we have started to address how these balances are perturbed by various immune and chemotherapies in short- and long-term experiments and preliminary data will be presented.
Citation Format: Febe van Maldegem, Karishma Valand, Victoria Tsang, Edurne Mugarza, Deborah Caswell, Philip Hobson, Julian Downward. Deep immunoprofiling of mouse lung cancer models in steady state and upon drug treatment. [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A160.
Abstract A168: Quiescent stem cells evade immune surveillance
Authors: Agudo Judith , Merad Miriam , Brown Brian D. 
Published: February 2019

Abstract
There is a long-standing interest in understanding the immunogenicity of adult stem cells due to their role in tissue homeostasis, regeneration and oncogenesis. Notably, their self-renewing capacity means they are long-lived, and can accumulate mutations over time, which would result in neoantigens. These neoantigens could make stem cells potential targets of T-cells. However, whether they are subject to immune surveillance is unknown. Here, we utilized a novel technology to study immune responses against virtually any cell type, along with specific stem cell mouse models, to interrogate the immunogenicity of adult stem cells in their niche in vivo. We found that immune privilege is not a general property of adult stem cells. Instead, our studies revealed that most epithelial stem cells, such as those in the gut and ovary, are subjected to immune clearance, but that highly quiescent stem cells escape immune detection. This is an intrinsic property of the resting stem cells resulting from downregulation of MHC class I and other key components of the antigen presentation machinery, which results in complete protection from immune attack. These studies established that quiescent tissue stem cells hide from immune surveillance and protect their integrity. This helps to understand why mutations in long-lived stem cells do not lead to immune clearance and suggests how cancer stem cells may evade immune surveillance.
Citation Format: Judith Agudo, Miriam Merad, Brian D. Brown. Quiescent stem cells evade immune surveillance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A168.
Abstract A178: Nr4a transcription factors limit CAR T-cell function in solid tumors
Authors: Chen Joyce , Scott-Browne James P. , Lopez-Moyado Isaac F. , Hempleman Laura J. , Seo Hyungseok , Sekiya Takashi , Yoshimura Akihiko , Rao Anjana 
Published: February 2019

Abstract
In cancer immunotherapy, CD19-targeted CAR T-cells have exhibited impressive clinical efficacy against B cell leukemias and lymphomas; however, they have been less effective against solid tumors. This is in part because CAR T-cells enter a hyporesponsive (“exhausted” or “dysfunctional”) state that is triggered by chronic antigen stimulation and characterized by upregulation of several inhibitory receptors and loss of effector function. To identify transcriptional regulators and other candidates contributing to the diminished function of CAR T-cells in solid tumors, we developed a CAR T-cell model in which recipient mice bearing murine melanoma tumors expressing the human CD19 antigen were adoptively transferred with CD19-targeted CAR T-cells. Genome-wide analyses of these mouse tumor-infiltrating lymphocytes (TILs) showed that endogenous CD8+ TILs and CAR T TILs selected for expression of high levels of PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of the Nr4a nuclear receptor family of transcription factors by the transcription factor NFAT. We demonstrate that in both CAR T TILs and endogenous CD8+ TILs, the Nr4a proteins Nr4a1 (Nur77), Nr4a2 (Nurr1), and Nr4a3 (Nor1) are prominent effectors of the transcriptional program downstream of NFAT: they promote the expression of inhibitory receptors and genes associated with early stages of the exhausted/ dysfunctional state, and limit effector function. Most importantly, treatment of tumor-bearing mice with CAR T-cells lacking all three Nr4a transcription factors (Nr4aTKO) resulted in tumor regression and prolonged survival. Nr4aTKO tumor-infiltrating CAR T-cells displayed a gene expression profile characteristic of effector function, including increased expression of granzymes, cytokines and the transcription factor T-bet. Many of these gene expression changes were associated with altered regulatory element accessibility near effector genes. Our data identify Nr4a transcription factors as major players in the cell-intrinsic program of T-cell hyporesponsiveness and point to Nr4a inhibition as a promising strategy for cancer immunotherapy.
Citation Format: Joyce Chen, James P. Scott-Browne, Isaac F. Lopez-Moyado, Laura J. Hempleman, Hyungseok Seo, Takashi Sekiya, Akihiko Yoshimura, Anjana Rao. Nr4a transcription factors limit CAR T-cell function in solid tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A178.
Abstract A179: Targeting UCP2 pathway in melanoma cells reprograms the tumor microenvironment and initiates antitumor immune cycle
Authors: Cheng Wan-Chen 
Published: February 2019

Abstract
Immune checkpoint blockade treatment displays promising therapeutic efficiency in different cancer types. However, a significant proportion of patients are refractory to this treatment due to lack of T-cell infiltration in tumors, a phenotype known as “cold tumors.” To improve the therapeutic benefits of checkpoint blockade, it is crucial to address how to escalate T-cell infiltration into tumors. Here, we characterized melanoma patients in The Cancer Genome Atlas (TCGA) into either high or low T-cell antitumor responses. We then identified the mRNA expression level of mitochondrial uncoupling protein 2 (UCP2) positively correlates with T-cell antitumor immune responses and prolonged patients survival. By using murine melanoma model, we revealed that overexpressing UCP2 in melanoma cells elevates CD8+ T-cell infiltration into the tumor microenvironment (TME) in a conventional type 1 dendritic cell (cDC1)-dependent manner and normalize tumor neovasculature. Mechanistically, UCP2 induction in tumor cells alters the cytokine milieu in tumors and stimulates the recruitment of cDC1 through a IRF5-CXCL10 chemokine axis. Hence, enhancing the expression of UCP2 in melanoma cells provides immunostimulatory shift by engaging the cDC1-CD8+ T-cell dependent antitumor immune cycle in the TME. Interestingly, we demonstrated that inducing UCP2 expression in melanoma cells by genetic approach or administration of rosiglitazone, an approved antidiabetic PPAR agonist, can sensitize PD-1 blockade-resistant melanomas to anti-PD-1 antibody treatment. Accordingly, our data indicate that targeting UCP2 in melanoma cells can be a potent strategy to increase antitumor response to checkpoint blockades in non-T-cell-inflamed tumors.
Citation Format: Wan-Chen Cheng. Targeting UCP2 pathway in melanoma cells reprograms the tumor microenvironment and initiates antitumor immune cycle [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A179.
Abstract A182: T-cell exhaustion assessment using a fully automated sequential chromogenic multiplex assay
Authors: Collignon Aurélie , Benchaaben Assil , Martirosyan Anna , Duval Matthieu , Bonzom Emilie , Prestat Emmanuel , Haond Christophe , Fieschi Jacques 
Published: February 2019

Abstract
Cancer immunotherapy by anti-PD-1 or anti-PD-L1 antibodies is now established as an efficient approach to restore the cytotoxic activity of exhausted T-cells. However, the strong and durable response observed in non-small cell lung cancer (NSCLC) patients is limited to a fraction of the treated population. Biomarkers, such as PD-L1 expression on tumor cells or tumor mutational burden, are approved as predictive markers of the response to anti-PD-1 or anti-PD-L1 antibodies. However, they are far from perfect to select patients eligible to immunotherapy. Since exhausted T-cells express more than one checkpoint inhibitor, it is hypothesized that an anti-PD1 antibody may not be sufficient to restore the activity of exhausted cells. Multiplex detection of the major immune checkpoints, i.e., PD-1, LAG-3 and TIM-3, on T-cells within the tumor microenvironment could, on one hand, predict the poor response to a single agent and could, on the other hand, predict the best combination of antibodies targeting more than one immune checkpoint. Here we present an automated sequential chromogenic multiplex assay allowing the assessment of the expression of PD-1, LAG-3 and TIM-3 on CD3+/CD8+ cells on a single FFPE tumor tissue section. Briefly, a tissue section is sequentially stained, digitized, unstained and restained with antibodies targeting the five markers. Images of the whole slide are then analyzed by digital pathology. First, a newly developed software is used to co-register the 5 virtual slides and perform colors deconvolution. Detection of positive cells is performed for each marker independently, using Indica Lab’s HALO software. Then, individual cells can be analyzed to identify complex phenotypes and assess their density on the entire tissue section. In addition, tissue segmentation tools are used to assess densities of exhausted T-cells expressing the major immune checkpoints in parenchyma, tumor stroma and invasive margin regions. The quantitative evaluation of T-cells’ exhaustion based on the expression of more than one immune checkpoint could improve patient stratification and lead to individualized combinations of immunotherapy agents.
Citation Format: Aurélie Collignon, Assil Benchaaben, Anna Martirosyan, Matthieu Duval, Emilie Bonzom, Emmanuel Prestat, Christophe Haond, Jacques Fieschi. T-cell exhaustion assessment using a fully automated sequential chromogenic multiplex assay [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A182.
Abstract A190: Mechanisms governing Foxp3-dependent and -independent gene expression in regulatory T-cells in evolutionary distant mice
Authors: Glasner Ariella , Zhong Yi , Veeken Joris Van Der , Rudensky Alexander 
Published: February 2019

Abstract
T regulatory (Treg) cells expressing the forkhead box transcription factor (Foxp3) are important regulators of immunity and play a key role in cancer and metastasis by controlling the activity of effector T-cells. Lineage-specifying transcription factors (TFs) establish cell identity and maintain cell specific transcriptional programs. Foxp3 is a key master TF controlling various Treg cell developmental and functional modalities. Foxp3 deficiency in humans and mice causes a life threatening autoimmune disease, and the enforced expression of Foxp3 in CD4+ T-cells confers suppressor functions. However, our understanding of Treg cell regulation during differentiation in the thymus, and in mature Treg cells in the periphery, whether Foxp3 dependent or independent, is still lacking. Single-nucleotide polymorphism (SNPs) may occur within coding genes or noncoding genomic regulatory areas and can have severe phenotypic consequences. We have recently attempted to link SNPs with differential Treg transcriptomic and epigenetic features in humans. However, such studies are limited by their intrinsic correlative nature, and by the limited number of SNPs. Here we use evolutionally distant mice strains C57Bl/6 (B6), CAST/EiJ (Cast) and SPRET/EiJ (Spret), to identify allele-specific imbalances and functional differences in the transcriptional and epigenetic programs during differentiation and in various conditions of Treg cells and their precursors. Using Foxp3 reporter and conditional knockout (KO) systems combined with interbreeding of the evolutionary distant mice strains in vivo, we explore the genetic and molecular mechanisms of Treg cell differentiation and function, employing high-throughput genomic methods including RNA-seq, ATAC-seq and Chip-seq. Such studies may pave a way for the development of novel therapeutic approaches to treat cancer and metastasis.
Citation Format: Ariella Glasner, Yi Zhong, Joris Van Der Veeken, Alexander Rudensky. Mechanisms governing Foxp3-dependent and -independent gene expression in regulatory T-cells in evolutionary distant mice [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A190.
Abstract A201: Single-cell resolution profiling of tumor-reactive CD4 T-cells reveals immune landscape alterations
Authors: Magen Assaf , Nie Jia , Ciucci Thomas , Zhao Yongmei , Mehta Monika , Tran Bao , Hannenhalli Sridhar , Bosselut Rémy 
Published: February 2019

Abstract
T-cell responses to tumors are typically neutralized through a variety of mechanisms. While cytotoxic CD8 cells have been the focus of most efforts to exploit T-cell responses against tumors, recent studies have demonstrated the clinical potential of the CD4 tumor-infiltrating lymphocytes (TILs). However, the functional diversity characteristic of these cells has limited our ability to harness CD4 TILs to fight tumors. To address this issue, we have used new experimental strategies to characterize the heterogeneity of the antitumor CD4 response in vivo, combining (i) tracking of CD4 T-cells specific for a defined recombinant tumor antigen, both in the tumor microenvironment and draining lymph node (dLN), (ii) genome-wide mRNA sequencing at the single-cell level (scRNAseq) and (iii) new computational approaches to increase the resolution of subpopulations discovery and uncover robust transcriptional changes across populations. We find novel subpopulations of regulatory (Treg) and effector (Th1) TILs expressing diverse co-inhibitory gene programs unique to the tumor microenvironment. In contrast to TILs composition, we find an unexpected Follicular helper (Tfh)-like cells and non-classical Th1 response in dLN. Comparison of TIL subpopulations to those defined in an immune response to viral infection (LCMV) reveals gene expression patterns unique to cancer. Our study uncovers previously unknown CD4 T-cell effector programs that provide ineffective responses and fail to control tumor progression. Targeting these programs should provide new options for the design of improved immunotherapy strategies.
Citation Format: Assaf Magen, Jia Nie, Thomas Ciucci, Yongmei Zhao, Monika Mehta, Bao Tran, Sridhar Hannenhalli, Rémy Bosselut. Single-cell resolution profiling of tumor-reactive CD4 T-cells reveals immune landscape alterations [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A201.
Abstract A205: Effects of anti-CTLA-4 and anti-PD-1 on memory T-cell differentiation and resistance to tumor relapse
Authors: Mok Stephen , Duffy Colm R. , Anang Nana-Ama A.S. , Allison James P. 
Published: February 2019

Abstract
Both anti-CTLA-4 and anti-PD-1 mediate significant response rates in cancer patients. As a hallmark of successful immunotherapies, they also mediate durable responses that last for years. For example, anti-CTLA-4 mediates a 22% 10-year overall survival rate, while anti-PD-1 mediates a 34% 5-year overall survival rate. Because of the broader uses of immunotherapies, the number of patients who have tumor relapse also increases. About 25% of patients who initially responded to anti-PD-1 have tumor relapse within 24 months. However, the relationship between tumor relapse and long-term effect of immunotherapies is still not clear. The goal of this study is to understand the differential effect of anti-CTLA-4 and anti-PD-1 on memory T-cell differentiation in murine tumor models. By rechallenging mice with tumor cells that have had tumors previously eradicated by either treatment, our results have shown that anti-CTLA-4 induces a more durable memory antitumor response compared to that treated with anti-PD-1. By tracing the antigen-specific CD8 T-cells throughout the memory phase, anti-CTLA-4 increases the frequency and cytokine production of antigen-specific T-cells compared with anti-PD-1. We have also found that anti-CTLA-4 induces the population of KLRG1+ effector CD8 T-cells among the effectors compared with anti-PD-1 during rechallenge, despite the ratio between central memory and effectors remaining the same. Our studies enable us to identify the long-term effect of immunotherapies on immune system.
Citation Format: Stephen Mok, Colm R. Duffy, Nana-Ama A.S. Anang, James P. Allison. Effects of anti-CTLA-4 and anti-PD-1 on memory T-cell differentiation and resistance to tumor relapse [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A205.
Abstract A213: Exploit the zebrafish to study lymphocyte infiltration in MYCN-amplified neuroblastoma
Authors: Qin Xiaodan , Lam Andrew , Feng Hui 
Published: February 2019

Abstract
Neuroblastoma is one of the most common pediatric solid tumors that derives from sympathetic nerve ganglia. Children with MYCN-amplified tumors have a very poor prognosis. MYCN amplification is associated with impaired inflammatory profiles and reduced numbers of tumor-infiltrating cytotoxic T-lymphocytes (CTL). However, it remains elusive how MYCN blocks the trafficking of T-cells to tumors and protects tumor cells escaping from CTL-mediated cytotoxicity. Elucidation of the mechanism by which MYCN suppresses immune surveillance in the neuroblastoma microenvironment could lead to improved treatment outcomes through immunotherapy. We generated a zebrafish model, in which lymphocytes and tumor cells were differentially labeled with red and green fluorochromes. We monitored these fish for trafficking of mCherry-labeled lymphocytes to EGFP-positive MYCN-overexpressing premalignant neural crests on 5, 14, and 21 days post fertilization (dpf). We found that MYCN-overexpressing premalignant neural crests could attract lymphocytes in living fish. To observe lymphocyte infiltration in different stages of tumor development, we will perform cryosection and quantify lymphocyte infiltration in each stage of tumor development. While this zebrafish model is useful in studying the behaviors of immune cells at different stages of tumor development, it can be further exploited to understand how MYCN regulates immune escape and how immune cell infiltration can be enhanced in MYCN-amplified neuroblastoma to suppress tumor onset and progression. This knowledge is critical for development of more efficient immunotherapies in treating children with neuroblastoma.
Citation Format: Xiaodan Qin, Andrew Lam, Hui Feng. Exploit the zebrafish to study lymphocyte infiltration in MYCN-amplified neuroblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A213.