bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B3: CD39+ cancer cells mediate immunosuppression reverted by CD39-blocking antibodies.
Authors: Regairaz Anne , Laheurte Caroline , Bonnefoy Nathalie , Eliaou Jean-Francois , Alberici Gilles , Bensussan Armand , Bastid Jeremy 
Published: August 2014

Abstract
The CD39 and CD73 ectonucleotidases hydrolyze extracellular ATP and ADP into immunosuppressive adenosine that binds adenosine receptor and inhibits T cell and NK cell responses. It has been demonstrated that CD39+ Tregs are increased in some human cancers and participate to immunosuppression. The importance of CD39+ Tregs in promoting tumor growth and metastasis has been evidenced in several models in vivo (for a review, see Bastid J et al., Oncogene, 2012). Here, we addressed whether CD39 is expressed by tumor cells and whether CD39+ tumor cells mediate suppression through the CD39-adenosine pathway. Immunohistochemical staining of normal and tumor tissues revealed that CD39 is upregulated in several types of human cancer. In cancer specimens, CD39 is expressed by infiltrating lymphocytes, tumor stroma and tumor cells, whereas its expression in normal samples is absent or weak and mostly limited to vascular endothelia. The expression of CD39 at the cell surface of tumor cells was further directly demonstrated by flow cytometry in human cancer cell lines. We evidenced that CD39+ tumor cells express functional CD39 and inhibit CD4 and CD8 T cell function in a CD39-dependant manner. Treatment with CD39-blocking antibodies was able to alleviate CD39+ tumor cell-mediated inhibition of CD4 and CD8 T cells in co-culture experiments. In conclusion, interfering with the CD39-adenosine pathway could represent a novel immunotherapy strategy for inhibiting Treg and tumor cell-mediated immunosuppression. Furthermore, these results support the ongoing development of CD39-blocking monoclonal antibodies as potential anticancer drugs.
Citation Format: Anne Regairaz, Caroline Laheurte, Nathalie Bonnefoy, Jean-Francois Eliaou, Gilles Alberici, Armand Bensussan, Jeremy Bastid. CD39+ cancer cells mediate immunosuppression reverted by CD39-blocking antibodies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B3.
Abstract B37: The heat shock protein receptor CD91 is necessary for tumor antigen cross-priming in vivo.
Authors: Zhou Yu Jerry , Binder Robert J. 
Published: August 2014

Abstract
Immunosurveillance mechanisms of tumors depend on the host's ability to cross-prime minute quantities of tumor antigens. We have investigated the role of tumor-derived heat shock proteins (HSPs) in transfer of tumor antigens from tumor cells to antigen presenting cells for two reasons; 1) HSPs are known to chaperone peptides in the cells. The chaperoned peptides reflect the entire antigenicity of the cell from which they are derived. 2) HSPs activate antigen presenting cells resulting in the provision of co-stimulatory molecules and cytokines. These two events require the cell surface receptor CD91 that is expressed on APCs. Here we have used a combination of CD91 inhibitors and CD91 knock-out mice to demonstrate that the HSP-CD91 interaction is crucial for developing concomitant immunity routinely seen in the tumor bearing host. This pathway is indispensable for cross-presentation when antigen levels are low. Considering that elevated levels of endogenous CD91 inhibitors have been reported in colon cancer patients, we propose a novel mechanism of immune evasion for tumors expressing competing ligands for immune receptors such as CD91.
Citation Format: Yu Jerry Zhou, Robert J. Binder. The heat shock protein receptor CD91 is necessary for tumor antigen cross-priming in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B37.
Abstract B39: Activated B cells infiltrate lung cancer.
Authors: Bruno Tullia C. , Kern Jeffrey , Slansky Jill E. 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer death in men and women, both in the United States and the world. The current 5-year survival rate for lung cancer in the United States is 16%, which can be attributed to the fact that the majority of lung cancer subjects present with late-stage disease that is not curable by current therapies i.e. chemotherapy and radiation. However, in the last several years, novel therapies have emerged to make lung cancer therapy better tolerated and more effective. We are particularly interested in developing an immunotherapy that will help to engage the immune system in targeting and destroying tumor cells. In a comprehensive survey of the immune infiltrate in non-small cell lung cancer (NSCLC) patients, we found that the frequency and total numbers of B cells (TIL-Bs) in the tumor versus the tumor-adjacent tissue was increased in comparison to other immune subsets, specifically, CD4, CD8, and regulatory T cells as well as NK and NKT cells. Further, these TIL-Bs were activated (CD21lo and CD69+), proliferated, and acquired a memory phenotype (CD27+). To test the function of the TIL-Bs, we are determining the types of cytokines they produce, their ability to secrete total IgG, and their potential to present antigen to CD4 T cells. Preliminary studies indicate that these cells generate activation cytokines (IFN-γ and IL-12) rather than suppressive cytokines, which suggests that the TIL-Bs have an effector phenotype that could aid in targeting the tumor. In addition, we are exploring why the TIL-Bs migrate to the site of the tumor. Preliminary data suggest that the common B cell chemokine receptors (CXCR3, CXCR4, CXCR5, CXCR7) are not elevated in TIL-Bs in the tumor compared to tumor adjacent tissue. However, normal peripheral blood B cells migrate toward tumor cell supernatant compared to tumor adjacent cell supernatant, which leads to the hypothesis that the tumor microenvironment generates more chemokines that attract TIL-Bs to the site of the tumor. Ultimately, we aim to identify a novel target for an immunotherapy clinical trial in lung cancer patients.
Citation Format: Tullia C. Bruno, Jeffrey Kern, Jill E. Slansky. Activated B cells infiltrate lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B39.
Abstract B46: Immunotherapy of solid tumors with IgE antibodies: Paradigm of a novel concept towards clinical application.
Authors: Karagiannis Sophia N. , Josephs Debra H. , Karagiannis Panagiotis , Saul Louise , Gilbert Amy E. , Dodev Tihomir , Koers Alexander , Blower Philip J. , Beavil Andrew J. , Nestle Frank O. , Spicer James F. , Gould Hannah J. 
Published: August 2014

Abstract
Developing therapeutic antibodies with enhanced effector functions may be key to improving clinical outcomes in cancer. Our strategy to address this entails engineering antibodies directly targeting tumor antigens and bearing Fc regions of the IgE antibody class. Numerous attributes of this class, such as natural immune activatory functions in tissues and high affinity for cognate receptors on frequently tumor-resident effector cells can translate into effector cell activation and superior protection against solid tumors, compared to the conventionally-used antibodies with IgG Fc regions. We have developed a paradigm for this concept, the antibody MOv18 IgE, against the tumor antigen Folate Receptor α. This agent is presently prepared for first-in-man clinical studies, having demonstrated superior efficacy compared to the corresponding IgG1 antibody in three in vivo models of cancer, including one in an immunocompetent host. The antibody also yielded very promising safety profiles in in vivo evaluations, and also in ex vivo readouts normally applied in the field of allergy to examine sensitivity to allergens. The latter studies, conducted using cancer patient blood, suggest that this antibody is unlikely to trigger Type I hypersensitivity in patients. We have now extended the pathway to the design of similarly potent antibodies for the treatment of other solid tumors such as malignant melanoma and breast carcinoma. Two antibodies with Fc regions of the IgG1 and IgE classes and the same specificity for CSPG4, a tumor antigen expressed by 80% of melanomas, were tested in a xenograft model of human melanoma in a humanized host, with evident superior efficacy for the IgE counterpart. On-going evaluations and planned clinical studies in patients with cancer will constitute important metrics of the concept of IgE antibodies in cancer therapy, will inform the emerging field of AllergoOncology and will provide new scope for the design of novel cancer therapies.
Citation Format: Sophia N. Karagiannis, Debra H. Josephs, Panagiotis Karagiannis, Louise Saul, Amy E. Gilbert, Tihomir Dodev, Alexander Koers, Philip J. Blower, Andrew J. Beavil, Frank O. Nestle, James F. Spicer, Hannah J. Gould. Immunotherapy of solid tumors with IgE antibodies: Paradigm of a novel concept towards clinical application. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B46.
Abstract B72: CD8αα+ langerin+ dendritic cells maintain the effector CD8 T cell population after adoptive transfer.
Authors: Gibbins John David , Hermans Ian , Petersen Troels 
Published: August 2014

Abstract
Adoptive cell transfer (ACT) is a promising new area of anti-cancer therapy. The process involves the isolation of T cells from a patient's blood, in vitro stimulation of the T cells against cancer antigens, then re-infusion of the activated cells back into the patient. This process provides a population of effector CD8 T cells capable of recognizing and killing cancer cells. ACT is currently limited by the ability of the transferred cells to survive in high numbers for an extended period of time and therefore overcoming this problem is a focus to improve the efficacy of the treatment.
The activation of cancer-specific CD8 T cells is dependent on the ability of dendritic cells (DCs) to acquire and present exogenous antigens on major histocompatibility complex class I (a process known as cross-presentation) for the stimulation of CD8 T cells. We have previously found a subset of splenic DCs expressing the CD8αα homodimer and the c-type lectin receptor langerin (CD207), that have a strong ability to activate CD8 T cells by cross-presentation. This DC subset is found in the marginal zone of the spleen, is highly efficient at phagocytosing apoptotic cells from the blood, and is believed to play an important role in scanning the blood for antigens. We therefore hypothesized that CD8αα+ langerin+ DCs influence the survival and expansion of adoptively transferred effector CD8 T cells in the blood.
Within this project we have used langerin-diphtheria toxin receptor mice, in which all langerin-expressing cells are ablated in vivo upon injection of diphtheria toxin, to address the role of the CD8αα+ langerin+ DC subset in maintaining the CD8 T cell population after ACT. For this purpose, we challenged mice intravenously with the T cell thymoma EG7.OVA and adoptively transferred in vitro activated OVA-specific CD8 T cells (OT-I T cells) 12 days later with or without prior langerin-DC depletion. We found a larger population of OT-I T cells when these were transferred into an EG7.OVA bearing host when compared to mice without tumors. Interestingly, mice that were depleted of their CD8αα+ langerin+ DCs did not develop this increase in OT-I T cell number and their absence resulted in reduced survival. Our data therefore suggest that antigen presentation by CD8αα+ langerin+ DCs play a role in sustaining high numbers of transferred CD8 T cells after ACT, resulting in increased protection against EG7.OVA. Manipulations that increase the stimulatory capacity of this DC subset could be a way to increase the efficacy of ACT therapy.
Citation Format: John David Gibbins, Ian Hermans, Troels Petersen. CD8αα+ langerin+ dendritic cells maintain the effector CD8 T cell population after adoptive transfer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B72.
Abstract B83: Targeting tumor-infiltrating macrophages decreases pancreatic tumor-initiating cells and improves chemotherapeutic responses by relieving immune suppression.
Authors: Mitchem Jonathan B. , Brennan Donal J. , Sanford Dominic E. , Knolhoff Brett L. , Zhu Yu , Brian Belt , Wang-Gillam Andrea , Goedegebuure Peter , Linehan David C. , DeNardo David G. 
Published: August 2014

Abstract
Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Far from being a static cell population, the presence of cancer stem cells appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact that immune responses have on the differentiation or expansion of tumor stem cells is not well understood. In this study, we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by either inhibition of colony stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. We also found that tumor-educated macrophages could directly enhance the tumor-initiating capacity of pancreatic tumor cells through the activation of signal transducer and activator of transcription 3 (STAT3). In turn, these STAT3-activated tumor-initiating cells facilitate macrophage-mediated suppression of CD8+ T lymphocytes. These data suggest that targeting tumor-infiltrating macrophages is an effective strategy for overcoming therapeutic resistance due to the presence of tumor-initiating cells.
Citation Format: Jonathan B. Mitchem, Donal J. Brennan, Dominic E. Sanford, Brett L. Knolhoff, Yu Zhu, Belt Brian, Andrea Wang-Gillam, Peter Goedegebuure, David C. Linehan, David G. DeNardo. Targeting tumor-infiltrating macrophages decreases pancreatic tumor-initiating cells and improves chemotherapeutic responses by relieving immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B83.
Abstract B88: Clinical significance of FOXP3+ T cell heterogeneity in ovarian cancer.
Authors: deLeeuw Ronald J. , Kost Sara E. , Nelson Brad H. 
Published: August 2014

Abstract
Background: CD8+ tumor-infiltrating lymphocytes (TIL) are associated with survival in ovarian cancer. A second subpopulation of TIL – defined by FoxP3 expression – has been reported to inhibit tumor immunity, resulting in decreased patient survival. However, recent studies by our lab and others have challenged this paradigm by showing that FoxP3+ T cells, in some patient cohorts, are associated with favorable prognosis.
Hypothesis: FoxP3 expression encompasses heterogeneous populations of effector and regulatory T cells that vary in proportion between patients and provide differential prognostication.
Methodology: We used multi-parameter flow cytometry to assess CD25, CD28, CD39, CD45RO, CD103, CD127, CTLA-4, CCR4, CCR7, GITR, Helios, ICOS, IFN-gamma, and PD-1 in CD3+CD4+CD8-FoxP3+ TIL in 12 patients with high-grade serous ovarian cancer (HGSC). CD4 and CD8 expression within FoxP3+ TIL was assessed by four channel multi-parameter immuno-histochemistry (mIHC). CD8-FoxP3+ TIL were assessed for CD25 and CD39 expression by mIHC. Survival analysis will be assessed via Kaplan-Meier plots, log-rank tests and Cox regression analyses.
Results: Consistent with prior reports, flow cytometry revealed that FoxP3 was expressed predominantly by CD4+ TIL. All CD4+FoxP3+ cells also expressed CD28, CD45RO, ICOS and CTLA-4, while they lacked expression of CD103 and IFN-gamma. However, we observed highly varied expression of regulatory T cell markers, including CD25, CD39, and GITR. Furthermore, on average, 4% (range 0-25%) of FoxP3+ TIL were CD8+. TCR spectratyping revealed similar TCR Vβ usage patterns between FoxP3- and FoxP3+ TIL. Although mIHC confirmed the variable expression of CD39 in CD8-FoxP3+ TIL, the expression of CD39 by a portion of HGSC tumors eliminated our ability to assess the clinical significance of this subset. The clinical significance of CD25 expression in CD8-FoxP3+ TIL is currently being analyzed in 245 cases of HGSC by mIHC.
Conclusions: FoxP3+ TIL demonstrate profound phenotypic heterogeneity within and between HGSC patients. FoxP3- and FoxP3+ TIL appear to be clonally related, suggesting their distinct phenotypes reflect microenvironmental influences rather than developmental origin or antigen specificity. The variable expression of CD25 and CD39 may be of importance in defining clinically important FoxP3+ TIL subsets. Further study of FoxP3+ TIL subpopulations in HGSC is required to better understand their contributions to tumor immunity and patient survival.
Citation Format: Ronald J. deLeeuw, Sara E. Kost, Brad H. Nelson. Clinical significance of FOXP3+ T cell heterogeneity in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B88.
Abstract IA14: Investigating the ICOS/ICOSL pathway as a target for combination therapy with anti-CTLA-4.
Authors: Sharma Padmanee 
Published: August 2014

Abstract
Biomarker studies used with immunotherapeutic strategies in the clinic have typically involved monitoring immunologic changes within the systemic circulation; however, recent data indicate that immunological changes within tumor tissues will be more likely to predict clinical responses. To obtain such data we conducted the first pre-surgical clinical trial with anti-CTLA-4 (ipilimumab) in a cohort of patients with localized bladder cancer. We are also conducting the first combination therapy pre-surgical trial with ipilimumab plus leuprolide acetate in patients with localized prostate cancer. Immunological data from these trials are obtained from both tumor tissues and blood samples.
We found an increased frequency of CD4 and CD8 T cells expressing high levels of inducible costimulator (ICOS) and decreased frequency of FOXP3-expressing CD4 T cells within tumor tissues of treated patients. The CD4+ICOShi population contained effector T cells that produced IFN-γ and recognized the cancer-testis antigen NY-ESO-1 expressed on tumor cells. We therefore identified ICOS as marker of a subset of effector T cells that is increased in frequency after anti-CTLA-4 therapy. ICOS+ T cells are being explored as both a pharmacodynamic marker for treatment with anti-CTLA-4 as well as a novel target to improve the efficacy of anti-CTLA-4 therapy.
These observations led us to test the possibility that engagement of ICOS could enhance the efficacy of anti-CTLA-4 therapy. To this end we transduced mouse B16F10 melanoma cells with a cDNA encoding ICOSL or a control construct. B16-ICOSL+ cells (IVAX) and control B16 cells were irradiated and used alone or in combination with anti-CTLA-4 to treat mice bearing established B16F10 tumors. We found that combination of the IVAX with anti-CTLA-4 was markedly more effective than the control vaccine plus anti-CTLA-4 or that of any single treatment alone. The increase in therapeutic efficacy was accompanied by a marked in increase in the density and functionality of CD4 and CD8 T cells within the tumor.
These results suggest a novel strategy for manipulating the immune system to enhance anti-tumor responses: checkpoint blockade coupled with provision of agonist signals to enhance costimulation mediated by ICOS.
Citation Format: Padmanee Sharma. Investigating the ICOS/ICOSL pathway as a target for combination therapy with anti-CTLA-4. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA14.
Abstract IA15: Role of PD-1 and LAG-3 in cancer immunotherapy.
Authors: Drake Charles G. 
Published: August 2014

Abstract
PD-1 and LAG-3 are negative regulatory molecules expressed on the cell surface of “exhausted” or non-functional CD8 T cells in both cancer and in infectious disease. In several cancer models, blocking both molecules shows a synergistic anti-tumor effect, without overt signs of autoimmunity. In more recent studies, we have examined the role of LAG-3 and/or PD-1 blockade on memory induction in vivo. Interestingly, we found that a short course (1 week) of combined antibody blockade results in a significant increase in the frequency of memory T cells over 30 weeks later. Augmented CD8 T cell responses were not apparent in the secondary lymphoid organs, but rather manifested as an increase in tissue resident responses. Responding cells in the combined blockade group also showed an increase in polyfunctional cytokine production, confirming the potential for increased effector function. Taken together, these data support our previous studies implying that simultaneous blockade of multiple immune checkpoints may be required for optimal anti-tumor immunity.
Citation Format: Charles G. Drake. Role of PD-1 and LAG-3 in cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA15.