bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B175: Semliki Forest virus-mediated oncolytic immunotherapy in mouse GL261 glioblastoma model
Authors: Martikainen Miika , Yu Di , Ramachandran Mohanraj , Fotaki Grammatiki , Martikainen Minttu-Maria , Merits Andres , Essand Magnus 
Published: February 2019

Abstract
Glioblastoma (GBM) is a devastating cancer of the central nervous system with no cure currently available. Oncolytic virotherapy with viruses that infect and destroy cancer cells provides a novel promising candidate therapy. We have previously shown that Semliki Forest virus (SFV) has therapeutic potency against orthotopic xenograft and syngeneic glioma models in mice. Here we show that SFV-infected cancer cells undergo immunogenic apoptosis, which triggers phagocytosis and maturation in co-cultured dendritic cells. SFV-killed GL261 mouse GBM cell lysate was also able to induce protective antitumor immune response in syngeneic mouse model, indicating that SFV oncolysis is immunogenic in vivo. By introducing mutations into the viral genome we have been able to produce a novel SFV clone which shows notably enhanced oncolytic potency in GL261 cells. As compared to the wild-type virus, the mutated SFV replicates faster and induces significantly stronger cytopathic effect. Robust viral replication and cytopathic effect were detected despite of activated type-I interferon signaling in the infected cells. This suggests that the enhanced SFV has increased resistance to antiviral response in mouse GBM cells. Viral proteins were detected by immunohistochemistry in orthotopic GL261 tumors after intratumoral injection of the mutated SFV virus. This provides evidence that the enhanced SFV is able to replicate in GL261 tumors in the face of antiviral in vivo microenvironment. Unwanted SFV replication in healthy brain cells can be inhibited by microRNA-mediated de-targeting. Taken together, the results indicate that oncolytic virotherapy with SFV can trigger antitumor immune responses, and support that SFV is a potent new candidate for oncolytic immunotherapy of GBM. These findings pave way for future clinical trials with oncolytic SFV.
Citation Format: Miika Martikainen, Di Yu, Mohanraj Ramachandran, Grammatiki Fotaki, Minttu-Maria Martikainen, Andres Merits, Magnus Essand. Semliki Forest virus-mediated oncolytic immunotherapy in mouse GL261 glioblastoma model [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 B175.
Abstract B182: Repurposing antiviral T-cells to fight tumors
Authors: Rosato Pamela C. , Wijeyesinghe Sathi , Stolley J. Michael , Nelson Christine , Davis Rachel L. , Manlove Luke S. , Pennell Christopher A. , Blazar Bruce R. , Chen Clark C. , Geller Melissa A. , Vezys Vaiva , Masopust David 
Published: February 2019

Abstract
Overcoming the immunosuppressive tumor microenvironment and localizing adoptive cell and checkpoint blockade therapies to solid tumors remain major impediments to successful cancer immunotherapy. Humans experience many viral infections. Once controlled, the host retains memory T-cells throughout the entire body to sense reinfection or recrudescence. Mouse models have demonstrated that when that same virus is reencountered, these T-cells sound an alarm that induces a local immunostimulatory environment that activates and recruits many arms of the immune system. We observed that, like healthy tissue, human tumors are commonly surveyed by memory T-cells specific for previously encountered viral infections. Antiviral T-cell immune surveillance of tumors was recapitulated in mouse cancer models. We tested and discovered that local delivery of adjuvant-free peptide, derived from previously encountered mouse viral infections, recapitulated the sensing and alarm T-cell function within the tumor: recruiting and activating both the innate and adaptive immune system. This approach induced intratumoral accumulation of granzyme B+ CD8+ T and NK cells, and activated dendritic cells within the tumor and subsequently within the tumor draining lymph node. In addition to stimulating the tumor microenvironment, preliminary data suggest activated antiviral T-cells directly killed peptide coated tumor cells. Viral peptide administration arrested rapidly growing and poorly immunogenic B16 melanomas in vivo and this treatment synergized with anti-PD-L1 checkpoint blockade to eliminate measurable tumors, and prevented recurrence in 34% of mice. Most cured mice rejected subsequent B16 tumor challenges at distant sites, indicating that effective systemic tumor-specific immunity was established. In support of the hypothesis that this approach could translate to human cancer immunotherapy, we found that viral peptide alarm therapy of freshly isolated human tumors drove similar immune activation to that observed in mice. This study demonstrates that natural and existing antiviral immunity can be repurposed to fight tumors without the need for adjuvant, vaccination, or personalized identification of immunogenic tumor neoantigens.
Citation Format: Pamela C. Rosato, Sathi Wijeyesinghe, J. Michael Stolley, Christine Nelson, Rachel L. Davis, Luke S. Manlove, Christopher A. Pennell, Bruce R. Blazar, Clark C. Chen, Melissa A. Geller, Vaiva Vezys, David Masopust. Repurposing antiviral T-cells to fight 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 B182.
Abstract B183: LFA-1 signals via Crk adapter proteins to induce actin-dependent T-cell migration and mechanosensing
Authors: Roy Nathan H. , MacKay Joanna L. , Buffone Alexander , Newell Krista , Robertson Tanner F. , Agarwal Sangya , Karimi Mobin , Hammer Daniel A , Burkhardt Janis K. 
Published: February 2019

Abstract
Allogeneic hematopoietic stem cell transplants (HSCT) are used to treat many malignancies, but the prevalence of graft-versus-host disease (GvHD) limits their overall success. Manipulating T-cell trafficking has emerged as an effective countermeasure, yet downstream integrin signaling pathways have yet to be targeted. We previously found that T-cells lacking the adapter proteins Crk and CrkL exhibit a robust antitumor response while causing little GvHD. We now find that T-cells from mice lacking Crk adapter proteins exhibit defects in LFA-1/ICAM-1 induced actin polymerization, leading edge formation, 2D migration, and integrin-mediated mechanosensing. Under shear flow, Crk/CrkL deficient T-cells fail to migrate upstream on ICAM-1 but migrate normally on VCAM-1, suggesting these integrin ligands relay different outside-in signals. Analysis of LFA-1 signaling reveals that Crk protein expression is required for phosphorylation of c-Cbl and its subsequent interaction with the PI3K subunit p85. Through this mechanism, Crk proteins promote PI3K activity and cytoskeletal remodeling downstream of LFA-1 engagement. Interestingly, this signaling pathway was largely specific to the LFA-1/ICAM-1 interaction, as WT-cells plated on VCAM-1 (which binds and signals through VLA-4) failed to induce high levels of phospho-Cbl, showed diminished PI3K activity, and did not migrate with a defined actin-rich leading edge. Finally, we show that knocking out CrkL alone is sufficient to alleviate GvHD, pointing toward unique roles of the Crk isoforms in T-cell biology. Together, these studies identify key signaling differences downstream of β2 vs β1 integrins that drive T-cell migratory behavior, and identify CrkL as an important factor during GvHD. Importantly, these data provide insight into integrin signaling that could be used to manipulate T-cell trafficking.
Citation Format: Nathan H. Roy, Joanna L. MacKay, Alexander Buffone Jr., Krista Newell, Tanner F. Robertson, Sangya Agarwal, Mobin Karimi, Daniel A Hammer, Janis K. Burkhardt. LFA-1 signals via Crk adapter proteins to induce actin-dependent T-cell migration and mechanosensing [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 B183.
Abstract B192: CD56 participation in immune effector cell activation and tumor cell eradication: A role for interleukin-15
Authors: Acker Heleen H. Van , Versteven Maarten , Reu Hans De , Ponsaerts Peter , Berneman Zwi N , Tendeloo Viggo F. Van , Smits Evelien L. 
Published: February 2019

Abstract
Oncoimmunologists are in a constant search for more effective immunotherapeutic treatments, helping to cure cancer. In this respect, immune cell participation is a key issue. A particularly interesting marker to identify antitumor immune cells is the neural cell adhesion molecule (NCAM), known as CD56. Namely, hematopoietic expression of CD56 seems to be confined to activated immune cells exhibiting some level of cytotoxic properties (Van Acker et al., Frontiers in Immunology 2017). Unfortunately, the current knowledge on the expression and functional role of CD56 is very fragmented. Therefore, we sought to elucidate the role of CD56 expression on various killer immune cells. First, we identified the high motility NCAM-120 isoform to be the main subset on immune cells. Next, through neutralization of surface CD56, we were able to demonstrate for the first time a direct involvement of CD56 in tumor cell lysis exerted by CD56-expressing killer cells such as natural killer cells, gamma delta (γδ) T-cells and interleukin (IL)-15-cultured dendritic cells (DCs). We also detected a putative crosstalk mechanism, suggesting CD56 as a co-stimulatory molecule in the interaction between IL-15 DCs and CD8 T-cells. Finally, by blocking the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K)–AKT pathway, with respectively trametinib and afuresertib, we confirmed our hypothesis that IL-15 stimulation directly leads to CD56 upregulation via the recruitment of shc, binding a phosphotyrosine residue on the IL-2/15Rβ chain. In conclusion, these results underscore the previously neglected importance of CD56 expression on immune cells, benefiting current and future immune therapeutic options.
Citation Format: Heleen H. Van Acker, Maarten Versteven, Hans De Reu, Peter Ponsaerts, Zwi N Berneman, Viggo F. Van Tendeloo, Evelien L. Smits. CD56 participation in immune effector cell activation and tumor cell eradication: A role for interleukin-15 [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 B192.
Abstract PR08: Mechanisms of primary resistance to PD-1 checkpoint blockade
Authors: Krogsgaard Michelle , Moogk Duane , Li Kaitao , Yuan Zhou , Osman Iman , Weber Jeffrey S , Zhu Cheng 
Published: February 2019

Abstract
Although much clinical progress has been made in harnessing the immune system to recognize and target cancer, there is still a significant lack of an understanding of how tumors evade immune recognition and the mechanisms that drive tumor resistance to both T-cell and checkpoint blockade immunotherapy. Our objective is to understand how tumor-mediated signaling through inhibitory receptors, including PD-1, combines to affect the process of T-cell recognition of tumor antigen and activation signaling. This has the goal of understanding the basis of resistance to PD-1 blockade and potentially identifying new molecular targets to enable T-cells to overcome dysfunction mediated by multiple inhibitory receptors. Biomembrane Force Probe (BFP) measurements show that that the activities of TCR-proximal signaling components affect T-cell mechanosensing and sensitivity at the earliest stages of antigen recognition and are influenced by PD-1 and other inhibitory receptors via Shp-1/2 by targeting CD28 and Lck to directly suppress TCR-pMHC-CD8 binding. Phospho-proteomics and flow cytometry-based analysis of patient-derived T-cells from PD-1 responders and nonresponders identified additional mediators, signaling components and pathways associated with PD-1 checkpoint blockade resistance. Targeting these interactions and understanding the basis of resistance to PD-1 blockade would potentially allow identification of novel biomarkers of resistance or new molecular targets to enable T-cells to overcome dysfunction during PD-1 checkpoint blockade.
Citation Format: Michelle Krogsgaard, Duane Moogk, Kaitao Li, Zhou Yuan, Iman Osman, Jeffrey S Weber, Cheng Zhu. Mechanisms of primary resistance to PD-1 checkpoint blockade [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 PR08.
Abstract PR16: Mucosal-associated invariant T-cells respond to the cutaneous microbiota and promote skin immunity
Authors: Constantinides Michael G. , Tamoutounour Samira , Linehan Jonathan L. , Sen Shurjo , Shaik Jahangheer , Roy Sobhan , Adams Erin J. , Belkaid Yasmine 
Published: February 2019

Abstract
Infectious agents are estimated to cause approximately 18% of cancers worldwide, supporting a link between microbial products and carcinogenesis. The diverse array of commensal microorganisms that reside at barrier sites of the human body, collectively termed the microbiome, provide the primary source of constitutive microbial stimulation and promote immune homeostasis through their release of microbial products, including derivatives of vitamin synthesis. Mucosal-associated invariant T (MAIT) cells are unconventional T-cells that recognize microbial-derived metabolites and provide an initial defense to pathogens through their rapid production of type-1 or type-17 cytokines. While MAIT-cells have been shown to infiltrate colorectal tumors, it remains to be determined how MAIT-cells contribute to tumorigenesis and whether commensals regulate MAIT-cell function. Here we show that MAIT-cells are a substantial skin-resident population capable of producing IL-17A. IL-23 signaling promotes the accumulation of cutaneous MAIT-cells and skin commensals induce local MAIT-cell proliferation and IL-1-dependent IL-17A production. In the absence of commensals, MAIT-cells are dramatically decreased, indicating that the microbiota is necessary for the development of this population. Utilizing MAIT-cell-deficient mice, we demonstrate that cutaneous MAIT-cells promote wound healing and inhibit the colonization of pathogens. This work identifies MAIT-cells as the only cell population that is entirely dependent on the microbiota and reveals the mechanism by which these cells respond to the commensal microbial community. Since IL-17A promotes tumor vascularization and neutrophil recruitment, the high frequency of MAIT-cells in human skin suggests that modulation of the skin-resident bacteria may have clinical applications for the progression of melanoma, and current studies are exploring this possibility using the B16 melanoma model in mice.This work was supported by the NIH Intramural Research Program. MGC is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute.
Citation Format: Michael G. Constantinides, Samira Tamoutounour, Jonathan L. Linehan, Shurjo Sen, Jahangheer Shaik, Sobhan Roy, Erin J. Adams, Yasmine Belkaid. Mucosal-associated invariant T-cells respond to the cutaneous microbiota and promote skin immunity [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 PR16.
Abstract A21: Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway
Authors: Jaiswal Ashvin R. , Bartkowiak Todd , Ager Casey R. , Chin Renee , Chen Chao Hsien , Budhani Pratha , Ai Midan , Reilley Matthew J. , Sebastian Manu M. , Hong David , Curran Michael A. 
Published: February 2019

Abstract
Purpose: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across multiple preclinical models of cancer. In the clinic, however, development of these agents has been stymied by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven anti-tumor immunity from hepatotoxicity.
Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immune competent mice, with or without co-administration of checkpoint blockade, via measurement of serum transaminase levels, through imaging of liver immune infiltrates, and via qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines and chemokines.
Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27, which is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage and their removal dramatically exacerbates 4-1BB agonist hepatitis. Co-administration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma.
Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation of myeloid cells to produce Interleukin-27. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis but yields equal or greater antitumor immunity.
Citation Format: Ashvin R. Jaiswal, Todd Bartkowiak, Casey R. Ager, Renee Chin, Chao Hsien Chen, Pratha Budhani, Midan Ai, Matthew J. Reilley, Manu M. Sebastian, David Hong, Michael A. Curran. Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A21.
Abstract A31: Reprogramming of tumor-associated macrophages by anti-Program Death Ligand 1 (PDL1)
Authors: Xiong Huizhong , Moskalenko Marina , Rodriguez Ryan , Mittman Stephanie , Yang Michelle , Kim Jeong , Barcelli Rafael Cubas 
Published: February 2019

Abstract
Tumor-associated macrophages play a vital role in shaping tumor environment and contribute to the cancer-immune set point. Immunotherapy such as aPD1/aPDL1 has demonstrated remarkable therapeutic efficacy on a variety of cancers through reinvigorating CD8+ T cells. However, its impact on macrophages largely remains unclear. Here by using mouse MC38 cancer model, we show that aPDL1 re-programs macrophages from M2-like to M1-like: it decreases Arginase-I (ARG1), an M2-like marker, and increases iNOS and MHCII, both M1-like markers, on macrophages. Next, we investigate the mechanism behind the reprogramming. We identify that IFNg from CD8+ T cells and NK cells is boosted by aPDL1 and is required for macrophage re-polarization. IFNg blockade abrogates this process. Finally, we examine additional cancer models and observe similar phenotypes in another aPDL1-responsive model, but not in a third, non-responsive model. We conclude that tumor associated macrophage is re-programmed from M2-like to M1-like following aPDL1 treatment, and that it is mediated by enhanced IFNg in the tumor environment. Our findings suggest macrophage reprogramming as a novel mechanism and an independent avenue to promote antitumor activity via modulation of the cancer-immune set point.
Citation Format: Huizhong Xiong, Marina Moskalenko, Ryan Rodriguez, Stephanie Mittman, Michelle Yang, Jeong Kim, Rafael Cubas Barcelli. Reprogramming of tumor-associated macrophages by anti-Program Death Ligand 1 (PDL1) [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A31.
Abstract A40: Prevalence of TIGIT expression in normal tissues, inflammation, and cancer
Authors: Hinsch Andrea , Kluth Martina , Lübke Andreas M. , Menz Anne , Krech Till , Steurer Stefan , Höflmayer Doris , Sauter Guido , Wilczak Waldemar , Fischer Kristine , Simon Ronald 
Published: February 2019

Abstract
Introduction: TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an immune checkpoint protein expressed on subsets of cytotoxic and regulatory T cells. TIGIT inhibiting drugs are currently being developed. The purpose of this study was to investigate the pattern of TIGIT expressing cells in normal tissues, inflammation and cancer.
Methods: Monoclonal mouse antibodies were used for immunohistochemical TIGIT (Dianova, Hamburg, Germany) and PD1 (Abcam, Cambridge, UK, ab52587) analyses on formalin fixed paraffin embedded tissue sections from normal lymphatic tissues as well as selected inflammations and cancers.
Results: In lymph nodes and tonsils, TIGIT positivity was seen in a large fraction of the germinal center T-cells. A high density of TIGIT positive T-cells also occurred in the marginal zone and in the interfollicular area. The analyses of selected inflammatory diseases revealed detectable TIGIT expression in a high proportion of T-lymphocytes in BCG induced cystitis and prostatitis, Hashimoto thyreoiditis, Lichen sclerosis of the penis, skin eczema, Crohn’s disease, and rheumatoid synovialitis. In all normal and inflammatory tissues, the pattern of TIGIT expression largely paralleled the pattern of PD1 expression. Three examples each of cancers types for which immune checkpoint inhibitors are already approved or extensively studied (melanoma, lung, kidney, bladder and colorectal cancer) were also analyzed. Here, the number of CD8 positive lymphocytes varied greatly between individual cases and the fraction of TIGIT and PD1 positive CD4 and CD8 positive lymphocytes varied considerably between cases.
Conclusion: Expression of TIGIT is regularly seen in a large subset of T-cells and has a similar expression pattern as PD1. TIGIT’s frequent co-expression with PD1 in cytotoxic T-cells is consistent with TIGIT representing a clinically relevant druggable immune checkpoint regulator that potentially could be targeted in combination with PD1.
Citation Format: Andrea Hinsch, Martina Kluth, Andreas M. Lübke, Anne Menz, Till Krech, Stefan Steurer, Doris Höflmayer, Guido Sauter, Waldemar Wilczak, Kristine Fischer, Ronald Simon. Prevalence of TIGIT expression in normal tissues, inflammation, and cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A40.