bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A61: Human BDCA3high dendritic cells infiltrate breast and ovarian tumors but are functionally altered
Authors: Hubert Margaux , Doffin Anne-Claire , Verronese Estelle , Durand Isabelle , Caux Christophe , Valladeau-Guilemond Jenny 
Published: March 2017

Abstract
Dendritic cells (DC) are key cellular players in the induction of antigen-specific anti-tumoral immunity. BDCA3high DC are equivalent to mouse CD8α+ DC and specialized for Ag cross-presentation. Interestingly, they are also the main producers of interferon-λ (IFN-λ), a recently discovered cytokine family with antiviral, anti-proliferative and anti-tumoral properties. In this study, we first demonstrated by multiparametric flow cytometry that human BDCA3high DC are present in breast and ovarian tumors. Secondly, we observed that their IFN-λ synthesis upon TLR3 activation is reduced compared to their blood equivalents. Using in vitro BDCA3high DC generated from CD34+ hematopoietic stem cells, we are currently deciphering mechanisms of this alteration. This study shows for the first time the infiltration of solid tumors by this rare DC subset and highlights a functional DC alteration which has to be taken into account in the design of new anti-tumoral immunotherapeutic strategies.
Grants: Ligue contre le cancer, ANRS, INCA (PL BIO2011-155)
Citation Format: Margaux Hubert, Anne-Claire Doffin, Estelle Verronese, Isabelle Durand, Christophe Caux, Jenny Valladeau-Guilemond. Human BDCA3high dendritic cells infiltrate breast and ovarian tumors but are functionally altered. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A61.
Abstract A66: Molecular profiling of regulatory T cells in a genetic mouse model of lung adenocarcinoma
Authors: Li Amy , Bhutkar Arjun , Joshi Nikhil S. , Jacks Tyler E. 
Published: March 2017

Abstract
The clinical success of immune checkpoint blockade in the treatment of various cancer types provides proof-of-principle that targeting immunosuppression in the tumor microenvironment is an effective therapeutic strategy. Regulatory T cells (Tregs) are a CD4+ T lymphocyte population that may play a dominant role in impairing anti-tumor immune responses. Characterized by their expression of the transcriptional regulator FOXP3, Tregs can inhibit adaptive immune responses through the production of inhibitory cytokines, direct cell killing, competition with other T cell subsets for antigen or other substrates, and suppression of antigen presentation. To recapitulate the strong immunosuppression observed in endogenous tumors, we have used an autochthonous, inducible mouse model of lung adenocarcinoma previously generated in the Jacks lab that is driven by expression of oncogenic KrasG12D and loss of p53 (KP model). Indeed, tumor development in the KP model is accompanied by an expansion of lung-resident Tregs, and previous work in the lab has shown that this population actively restrains anti-tumor T cell responses. In this study, we have transcriptionally profiled lung Tregs in the KP model to identify pathways to preferentially target Tregs in tumor-bearing lungs. We have shown that lung Tregs have a distinct transcriptional phenotype that shares characteristics with that of previously described “effector” Treg populations in a variety of tissue and inflammatory contexts. Furthermore, the KP lung Treg gene signature is associated with survival when applied to the bulk transcriptomes of various tumor types, and is better correlated with patient outcome in lung adenocarcinoma than a number of immune parameters, including mutation burden and expression of CD8A, FOXP3, and GZMA. Together, our data demonstrate that a gene expression signature drawn from cancer-associated Tregs with a distinct, functional phenotype may be useful as a biomarker for clinical outcomes in multiple tumor types.
Citation Format: Amy Li, Arjun Bhutkar, Nikhil S. Joshi, Tyler E. Jacks. Molecular profiling of regulatory T cells in a genetic mouse model of lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A66.
Abstract A70: Tumor growth enhancement under obese conditions: Role of intratumoral myeloid cells
Authors: al-Ramadi Basel K. , Kaimala Suneesh , Mohamed Yassir A. , Al-Sbiei Ashraf , Bashir Ghada , Fernandez-Cabezudo Maria J. 
Published: March 2017

Abstract
Obesity is a metabolic disorder characterized by a state of chronic inflammation. Based on epidemiological evidence, obesity has been linked to increased risk of developing several types of cancer. However, the mechanisms underlying this phenomenon remain unknown. Successful growth of cancer cells hinges on developing mechanisms to evade host immunosurveillance, particularly within the tumor microenvironment. In the current study, we utilized a high-fat-diet (HFD)-induced obesity mouse model to gain mechanistic insight into the effect of obesity on progression of implantable syngeneic tumors. When lean or obese mice were implanted with B16.F1 melanoma or MC38 colon carcinoma, tumor growth was more robust in obese group than lean controls, suggesting that obese conditions promote tumor growth. Multi-color flow cytometric analysis and gene expression profiling were carried out on distinct subpopulations of intratumoral myeloid cells. Tumors of lean mice had higher percentages of myeloid cells compared to obese counterparts with characteristics typical of activated inflammatory macrophages. In contrast, tumors of obese mice had disproportionately higher frequency of myeloid derived suppressor cells (MDSC) with a gene signature suggestive of immunosuppressive potential. These findings highlight the role of metaflammation in tumor growth promotion via the regulation of frequency and activation status of distinct subpopulations of intratumoral myeloid cells.
Citation Format: Basel K. al-Ramadi, Suneesh Kaimala, Yassir A. Mohamed, Ashraf Al-Sbiei, Ghada Bashir, Maria J. Fernandez-Cabezudo. Tumor growth enhancement under obese conditions: Role of intratumoral myeloid cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A70.
Abstract A75: Designed Ankyrin Repeat Proteins (DARPins) as recognition motifs in chimeric antigen receptors
Authors: Balakrishnan Ashwini , Salter Alexander I. , Plückthun Andreas , Riddell Stanley R. 
Published: March 2017

Abstract
Chimeric antigen receptors (CARs) consist primarily of single chain variable fragments (scFv) linked to the T cell activation (CD3ζ) and costimulatory domains. We investigated whether alternative recognition motifs selected for ligand binding from synthetic libraries of Designed Ankyrin Repeat proteins (DARPins) could be incorporated into CARs. As proof of principle, we linked a DARPin (DARPin E01) specific for EGFR to the CAR signaling domain and compared anti-tumor function with a high affinity CAR containing the Cetuximab scfv, which recognizes an overlapping epitope. Our in vitro results show that DARPin CARs designed with flexible linkers and with short and long spacer domains exhibit specific cytotoxicity, cytokine secretion and proliferation against EGFR+ targets that is comparable to the Cetuximab CAR. We tested DARPins CARs in an in vivo breast cancer tumor model with EGFR+ MDA-MB-231 tumor cells and found enhanced anti-tumor clearance with both E01 DARPin and Cetuximab scFV CARs. We show that an EpCAM-specific DARPin chimeric costimulatatory receptor (CCR) can also be used in conjunction with a scFV CAR targeting ROR1 to provide combinatorial antigen recognition and enhance T cell function against tumor cells expressing both targets. The EpCAM-specific DARPin CCR combined with first or second generation ROR1 scFv CARs enhanced T cell cytokine secretion and proliferation. The compact stable structure of DARPins should facilitate linking of multiple DARPins targeting different antigens reducing the likelihood of antigen loss. In summary, the stable structural scaffold of DARPins and the presence of diverse binder libraries make them attractive recognition motifs to incorporate into CARs.
Citation Format: Ashwini Balakrishnan, Alexander I. Salter, Andreas Plückthun, Stanley R. Riddell. Designed Ankyrin Repeat Proteins (DARPins) as recognition motifs in chimeric antigen receptors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A75.
Abstract A81: Adoptively transferred Chondromodulin 1/HLA-A:0201 allo-restricted T cell receptor transgenic CD8+ T cells are well tolerated and cause partial regression in a patient with disseminated Ewing Sarcoma
Authors: Thiel Uwe , Kirschner Andreas , Einspieler Ingo , Burdach Stefan 
Published: March 2017

Abstract
Background: Patients with Ewing sarcoma (ES) metastatic to bone and bone marrow (BM) do not survive irrespective of therapy. We assessed toxicity, viability, BM homing and anti-tumor activity of adoptively transferred HLA-A*0201/chondromodulin 1 (CHM1) allo-restricted T cell receptor (TCR) transgenic CD8+ T cells in an ES patient with refractory disease including marrow.
Patient and Methods: An twelve years old HLA-A2+ boy was diagnosed with ES of the right femur. After treatment according to the Euro-Ewing 2008 protocol he suffered early relapse 11 months after diagnosis. For relapse treatment he received MetaEICESS 2007 including consolidation with haploidentical stem cell transplantation (allo-SCT) from his HLA-A2- mother. Before and shortly after transplant the patient relapsed twice. Thereafter he suffered from progressive disease under combined rescue radiochemotherapy. Within one week after the last progression, he received 1 x 106/kg (1st transfer, d0) and 8.2 x 106/kg CHM1319-T cell receptor (TCR) transgenic donor CD8+ T cells (2nd transfer, d32; in combination with ipilimumab and nivolumab), respectively. A patient derived ES cell line was isolated.
Results: CHM1319-TCR transgenic donor T cells showed specific in vitro lysis of the patient's ES cell line. One week after 1st transfer, CHM1319-TCR transgenic T cells stained CHM1319 multimer positive in BM but negative in peripheral blood (PB). After 2nd transfer, BM of posterior iliac spines as well as PB stained CHM1319 multimer positive at a high rate and RT-PCR and flow-cytometric CD99+/CD45- ES phenotype as well as partial PET-signal reduction were noted. Five further metastatic bone/ marrow compartments showed significant PET signal regression. The patient never developed GvHD symptoms and died of disease 10 weeks after 1st transfer due to resistant lung metastasis.
Conclusions: CHM1319-TCR transgenic T cells home to affected BM and cause partial disease regression. These cells may proliferate in vivo for at least four weeks without causing GvHD.
Citation Format: Uwe Thiel, Andreas Kirschner, Ingo Einspieler, Stefan Burdach. Adoptively transferred Chondromodulin 1/HLA-A:0201 allo-restricted T cell receptor transgenic CD8+ T cells are well tolerated and cause partial regression in a patient with disseminated Ewing Sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A81.
Abstract B02: Immune events in the sentinel lymph node in melanoma predict local and systemic response to disease
Authors: Essner Richard , Gong Ke-Wei , Kaufman David Z. , Gangi Alexandra , Sim Myung Shin 
Published: March 2017

Abstract
Background: The sentinel node (SN) has become the standard diagnostic tool for staging cutaneous melanoma. With the recent development of anti-CTLA-4 and anti-PD-1 antibodies as immunotherapies we hypothesized that the early immune events in melanoma maybe first observed in the SN and be related to the response to disease.
Methods: 81 SN from 79 patients were evaluated with microarray technology, qPCR, routine H&E & IHC. We identified 10 immune genes that are present by qPCR in SNs from a random section of the SN. Statistical analysis assessed the utility of these markers to predict tumor-positive SN and survival.
Results: Of the 79 patients, 48 (61%) were men. Median age was 59 (range 6-95 years). Primary melanomas were most commonly from the trunk (51%) and extremities (40%). The median thickness of the primaries was 0.95mm. 13% of the patients had ulcerated primaries. 29% of the primary tumors had at least 1 mitosis/mm2 . 9 (11%) patients had SN metastasis, as determined by conventional H&E and IHC. The incidence of SN positivity was directly related to tumor thickness; the higher the T-stage the greater percentage of SN positivity: 2% T1, 19% T2, 20% T3 and 60% T4 melanoma. 33% of ulcerated primaries and 30% with increased mitotic rate had a tumor-positive SN. The microarray did not identify specifc immune related genes when comparing tumor-positive to tumor-negative SN. We then evaluated the gene expression of CD80, CD86, CD28, CD40, IDO, Arginase, IL-2, IL-10, PD-1 and CTLA-4 by qPCR. By univariate analyses: patient age (p&lt;0.001), primary site (&lt;0.001), decreasing gene expression of CTLA-4 (p&lt;0.001) and PD-1 (p&lt;0.001) in SN were predictive of SN positivity. Multivariate analyses confirmed the down-regulation of CTLA-4 and PD-1 gene expression in the SN were predictive of metastases in the SN and the AUC values of predicting SN positivity were 0.808 and 0.731 respectively . The positive and negative predictive values of the tests were 100 and 89.5%. Further the down-regulation of CTLA-4 and PD-1 gene expression in the SN correlated with diminished survival, while the up-regulation of IL-10 correlated with poor survival.
Conclusions: Our results demonstrate the significance of CTLA-4, PD-1 and IL-10 gene expression in the SN of melanoma patients. The expression of these genes may be early events in the immune dysfunction that occurs with melanoma metastases.
Citation Format: Richard Essner, Ke-Wei Gong, David Z. Kaufman, Alexandra Gangi, Myung Shin Sim. Immune events in the sentinel lymph node in melanoma predict local and systemic response to disease. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B02.
Abstract B06: Targeting M2-Tumor Associated Macrophages (M2-TAMs) in prostate cancer
Authors: Zarif Jelani C. , Hernandez James R. , Yang Weiming , Zhang Hui , Pienta Kenneth J. 
Published: March 2017

Abstract
Prostate cancer is a leading cause of cancer-related deaths of men in the U.S., and in the past year, over 30,000 men died from this disease. While localized prostate cancer is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Alternatively activated macrophages, also known as M2-macrophages, primarily scavenge debris and in the process, promote angiogenesis and wound repair. M2-macrophages are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) have been reported to associate with solid tumors such as prostate cancer to facilitate epithelial to mesenchymal transition (EMT), tumor invasiveness, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. The purpose of this project is to develop novel therapeutics that will directly target M2-TAMs for destruction and subsequently attenuate prostate tumor growth, progression, and metastasis. Our hypothesis is to determine if targeting of M2-TAMs by using enriched surface antigens that are targeted by antibody-drug-conjugates (ADCs), be an effective therapy for lethal prostate cancer while simultaneously eliciting an immune response. To identify novel surface antigens expressed on M2-macrophages, we developed a novel method of creating homogenous populations of human macrophages from CD14+ monocytes in vitro. Our homogenous M1 macrophages secrete pro-inflammatory cytokines and our M2 macrophages secrete anti-inflammatory cytokines as well as VEGF. We then performed solid-phase extraction of N-linked glycopeptides (SPEG) followed by liquid chromatography-tandem Mass Spectrometry (LC-MS/MS) on our homogenous macrophage populations. We discovered six novel peptides that are enriched exclusively on M2-macrophages relative to M1 macrophages and CD14+ monocytes. Lastly, we determined if these surface antigens, found enriched on M2 macrophages, were also expressed in human metastatic castrate-resistant prostate cancer (mCRPC). Using mCRPC tissues from rapid autopsies supplied by the Departments of Urology and Surgical Pathology, we were able to determine M2-macrophage infiltration by using immunohistochemistry and flow cytometry. The studies described here outline a method of altering the tumor immune microenvironment. By identifying specific markers on M2-TAMs, we predict that this method of targeting will provide a better prognosis for patients who have been diagnosed with lethal prostate cancer.
Citation Format: Jelani C. Zarif, James R. Hernandez, Weiming Yang, Hui Zhang, Kenneth J. Pienta. Targeting M2-Tumor Associated Macrophages (M2-TAMs) in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B06.
Abstract B17: Validation of targeted gene expression profiling panel for identifying biomarker signatures of immunotherapy responders
Authors: Pankov Aleksandr , Sun Yongming , Ku Yuan-Chieh , Tom Warren , Zheng Jianping , Looney Timothy , Au-Yong Janice , Hyland Fiona , Mongan Ann 
Published: March 2017

Abstract
Cancer immunotherapy has led to an unprecedented, long-lasting response in populations susceptible to the therapies. Despite the therapeutic potential, identifying biomarkers and stratifying populations that are likely to respond has been a challenge. Gene expression profiling has previously been successfully used to stratify individuals based on survival and treatment characteristics, but there exist limitations with the prevalent technologies. In particular, full transcriptome gene expression estimates use limited biological material to measure the concentrations of tens of thousands uninformative genes and often lack the depth required to accurately measure expression levels of lowly-expressed genes. These genes may be critical to the identification of a signature associated with immunotherapy responders. To efficiently measure the expression of the key genes potentially informative of an immunotherapy response, we developed a high-throughput targeted gene expression solution measured by our RNA Ion Oncomine Immune Response Profiling panel* containing 395 genes. This panel provides information about the expression of genes involved in tumor checkpoint inhibition (including CTLA4, PD-1, PD-L1, OX-40, 4-1BB, TIM3, LAG3) and other targets such as CSF1R, and IDO1, as well as additional markers of T cell signaling pathway, interferon signaling, and markers of tumor infiltrating lymphocytes (TIL). We used publicly available TCGA data to demonstrate the need and develop a solution for a new normalization procedure that allows for accurate comparisons of samples within various cancer types. Furthermore, we verified a linear and unbiased estimate of fold change in our assays across mixing concentrations of a cell-line titration experiment. Finally, by achieving a high correlation (r &gt; .99) of technical replicates, along with robust expression estimation even at low input amounts (10 ng RNA), our panel offers a valuable solution for biomarker research in cancer immunotherapy.
*For research use only. Not for use in diagnostic procedures.
Citation Format: Aleksandr Pankov, Yongming Sun, Yuan-Chieh Ku, Warren Tom, Jianping Zheng, Timothy Looney, Janice Au-Yong, Fiona Hyland, Ann Mongan. Validation of targeted gene expression profiling panel for identifying biomarker signatures of immunotherapy responders. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B17.
Abstract B25: Visualization of immune response to Hepatitis B vaccination by in vivo mouse imaging
Authors: Kim Ha , Hong Keejong , Ahn Byung Cheol , Yum Jung Sun , Youn Hyewon 
Published: March 2017

Abstract
By taking advantage of bioluminescence imaging to monitor luciferase expressing splenocytes from the luciferase transgenic mouse, we visulaized the enhancement of immune response against hepatitis B virus (HBV) vaccine with adjuvants. To visualize antigen in vivo, large hepatitis B virus antigen (L-HBsAg) was labeled with radioiodine (125I). B6 mice were intramuscularly vaccinated. The localization of 125I-L-HBsAg was monitored for 5 weeks using animal SPECT/CT. To monitor the immune response, the luciferase expressing splenocytes were injected intravenously into immunized B6 mice. Bioluminescence signals from splenocytes were measured by IVIS 100 system. Localization of inoculated L-HBsAg was successfully monitored using animal SPECT/CT. L-HBsAg was lasted for 5 weeks and diminished. In addition, the injected splenocytes were successfully visualized in immunized mice, homing to spleen within 30 minutes and were accumulated in lymph nodes within 5 hours. Accumulation of splenocytes at vaccination site was observed within 24 hours. Moreover, after 10 hours, mouse vaccinated with antigen and two adjuvants showed 4 times more accumulation of splenocytes at vaccination site compared to mouse vaccinated with antigen only. Six days later, mouse vaccinated with antigen and two adjuvants showed 1.7-4.73 fold increased luciferase intensity of splenocytes at spleen, lymph nodes and vaccination site compared to mouse vaccinated with antigen only. In conclusion, in vivo real-time bioluminescent monitoring of splenocytes homing and proliferation against vaccination successfully provides efficiency of adjuvants. Our imaging system can be used for evaluation of efficacy of vaccination by enhanced the proliferation and activation of splenocytes near the vaccination site.
Note: This abstract was not presented at the conference.
Citation Format: Ha Kim, Keejong Hong, Byung Cheol Ahn, Jung Sun Yum, Hyewon Youn. Visualization of immune response to Hepatitis B vaccination by in vivo mouse imaging. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B25.