bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A167: Prevalence of TREG cells and effects of their inhibition on growth of oral cancer cells
Authors: Aggarwal Sadhna , Sharma Suresh C. , Das Satya N. 
Published: February 2019

Abstract
Oral squamous cell carcinoma (OSCC) is one of the major cancers affecting Asian countries. The main causative factor has been tobacco habit. It has been reported that immune dysfunction in these patients is one of the major factors for tumor growth and dissemination that affects disease-free survival of the patients. We assessed the phenotypic and functional characteristics of regulatory T (Treg) CD4+CD25+FoxP3+subsets in patients with OSCC by multicoloured flow cytometry. Subsequently we investigated the effects their inhibition via TDG on growth of OSCC cell lines in vitro. An increased (p&lt;0.05) prevalence of Treg phenotypes (CD4+CD25+, CD4+FoxP3+, CD8+FoxP3+, CD4+CD25+FoxP3+) was observed in the peripheral circulation of OSCC patients that positively correlated with clinicopathologic features. The increased frequency of CD4+CD8+CD25+FoxP3+, a unique T-cell subset, CTLA4+, GITR+, NrP1+ and granzyme B+ (GzmB) Tregs also showed a significantly higher prevalence in OSCC patients. Functionally, CD4+FoxP3+ Tregs showed skewed expression of IL2, IL10 and IL35 in patients as compared with the normal controls. Higher expression of TGFβ in tumor tissues suggests their dominant role in the up regulation of differentiation of Tregs from naive T-cells in the tumor bearing host. Further, enhanced expression of CCR5 and CCR7 on Tregs with up regulation of their ligands (CCL5, CCL19 and CCL21) in tumor cells indicates efficient recruitment and trafficking of Tregs to the tumor site. Treatment with βGBP showed growth-promoting effects on Tregs and oral cancer cells. However, the treatment with its inhibitor TDG resulted in inhibition of Treg subsets and also decreased the frequency of IL10+ and IL35+ Tregs, indicating its immunomodulatory effects. Hence, it seems reasonable to assume that modulation of functional dynamics of selective Treg subsets may be useful in enhancing antitumor immunity and developing immunotherapeutic strategies for patients with oral squamous cell carcinoma.
Citation Format: Sadhna Aggarwal, Suresh C. Sharma, Satya N. Das. Prevalence of TREG cells and effects of their inhibition on growth of oral cancer cells [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 A167.
Abstract A176: Overcoming CD8 T-cell suppression in the tumor microenvironment
Authors: Cartwright Adam N.R , Jiang Peng , Saadatpour Assieh , Yuan Guo-Cheng , Liu Shirley X. , Wucherpfennig Kai W. 
Published: February 2019

Abstract
CD8 T-cell-mediated antitumor immunity is required for the control and elimination of tumors. However, tumors are able to overcome immune response resulting in immunosuppression, tumor growth, and metastatic spread. CD8 T-cells are controlled through a homeostatic network of positive and negative feedback loops. These negative signals are exploited by the tumor and associated suppressive cell populations in the tumor microenvironment. Immunotherapies targeted to receptors that control these negative signals, termed immune checkpoint inhibitors, have provided robust and durable responses to a number of cancers. Unfortunately, only a subset of patients will respond to current immunotherapies. This is due to the accruement of suppressive and inhibitory mechanisms employed by the tumor and its microenvironment. These include expression of inhibitory ligands, release of immune-suppressive factors, and the recruitment of suppressive cell populations. Furthermore, the administration of immune checkpoint inhibitors can enhance tumor acquisition of a more suppressive phenotype, diminishing immune responses through additional inhibitory pathways. We therefore propose that further CD8 T-cell-intrinsic negative regulators most likely exist, which can be targeted to improve antitumor responses. Here, we have used functional genomic approaches to identify pathways that can be targeted to advance anti-tumor responses, either in combination with anti-PD-1 or to overcome suppressive mechanisms employed by the tumor microenvironment. Using both in vivo and in vitro assays, we have identified both a novel target that provides an enhancement to CD8 T-cell effector function when in combination with PD-1 checkpoint blockade, and CD8 T-cell-intrinsic pathways that are modulated by the presence of suppressive cells associated with the tumor microenvironment.
Citation Format: Adam N.R Cartwright, Peng Jiang, Assieh Saadatpour, Guo-Cheng Yuan, Shirley X. Liu, Kai W. Wucherpfennig. Overcoming CD8 T-cell suppression in the tumor microenvironment [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 A176.
Abstract A177: Impact of regulatory T-cells on carcinogenesis of oral squamous cell carcinoma
Authors: Chao Jaime L. , Savage Peter A. 
Published: February 2019

Abstract
Although some head-and-neck squamous cell carcinomas (HNSCCs) are associated with human papillomavirus (HPV) infection, a large proportion of HNSCCs are HPV-negative and are characterized by mutational signatures associated with smoking, suggesting that HPV-negative HNSCCs are induced by carcinogen exposure. In many human cancers, including HNSCC, regulatory T (Treg) cells are found at elevated densities and are thought to be a major barrier to the generation of robust anti-tumor T-cell responses. However, recent studies indicate that Treg cells can serve diverse functions in non-lymphoid sites. Therefore, it is critical to elucidate the function of Treg cells infiltrating HNSCC lesions. To study the functional impact of Treg cells on the development and progression of HPV-negative HNSCC, we utilized an autochthonous mouse model of carcinogen-induced oral squamous cell carcinoma (SCC), in which mice are exposed long-term to the carcinogen 4-nitroquinoline-1-oxide (4-NQO) in the drinking water. Immunohistochemistry and flow cytometric analysis revealed elevated densities of CD3+ T-cells and Foxp3+ Treg cells in premalignant dysplastic lesions and SCC lesions within the tongue epithelium, suggesting that many lesions exhibit a T-cell-inflamed phenotype. Single-cell TCR sequencing demonstrated the presence of recurrent Treg cell clones within carcinogen-induced lesions, suggesting clonal expansion of Treg cells in the tumor microenvironment. Surprisingly, the systemic depletion of Treg cells at the later stages of carcinogen exposure did not induce tumor regression, but instead induced the opposite effect, driving increased incidence and burden of SCC. These findings suggest that Treg cells may play an unexpected role in restricting the progression of carcinogen-induced SCC in the oral cavity, prompting a re-examination of the common paradigm that Treg cells promote tumorigenesis by suppressing antitumor immunity. Clinically, our findings suggest that novel therapies could be developed to combat HNSCC by triggering the recruitment or activation of tumor-associated Treg cells, and suggest that checkpoint blockade therapies that induce intratumoral Treg cell depletion may have unintended adverse consequences.
Citation Format: Jaime L. Chao, Peter A. Savage. Impact of regulatory T-cells on carcinogenesis of oral squamous cell carcinoma [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 A177.
Abstract A189: Targeting T-cell epigenetic programs to enhance the efficacy of immune checkpoint blockade
Authors: Ghoneim Hazem E. , Fan Yiping , Moustaki Ardiana , Abdelsamed Hossam , Dash Pradyot , Dogra Pranay , Carter Robert , Awad Walid , Neale Geoff , Thomas Paul , Youngblood Ben 
Published: February 2019

Abstract
Immune checkpoint blockade (ICB)-mediated rejuvenation of exhausted T-cells has emerged as a promising approach for treating various cancers and chronic infections. However, T-cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. Given that many of the impaired effector properties of terminally exhausted CD8 T-cells appear to be heritably maintained even in the absence of antigen, we investigated the role of de novo DNA methylation programming as a T-cell-intrinsic mechanism for establishing the ICB-nonresponsive state of T-cell exhaustion. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T-cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo DNA methylation programs. Blocking de novo DNA methylation in activated CD8 T-cells allowed them to retain their effector functions despite persistent stimulation during chronic viral infection. We found that these de novo epigenetic programs are not only critical for establishing T-cell exhaustion, but also restrict T-cell expansion and clonal diversity during PD-L1 blockade treatment. Moreover, these exhaustion-associated DNA methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T-cell. Therapeutic approaches to reverse these programs enhanced antitumor CD8 T-cell responses and tumor control during PD-L1 blockade therapy. These data establish de novo DNA methylation programming as a major T-cell-intrinsic barrier of ICB therapy. Targeting T-cell epigenetic programs provides great potential for fostering more powerful T-cell immunotherapies. Reference: Ghoneim, et al. Cell 2017.
Citation Format: Hazem E. Ghoneim, Yiping Fan, Ardiana Moustaki, Hossam Abdelsamed, Pradyot Dash, Pranay Dogra, Robert Carter, Walid Awad, Geoff Neale, Paul Thomas, Ben Youngblood. Targeting T-cell epigenetic programs to enhance the efficacy of immune 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 A189.
Abstract A215: Thymocyte selection-associated HMG box protein TOX is a master regulator of tumor-specific T-cell dysfunction
Authors: Scott Andrew C. , Camara Steven , Lauer Peter , Synder Alexandra , Zamarin Dmitriy , Walther Tyler , Levy Olivier , Glickman Michael , Kaye Jonathan , Philip Mary , Schietinger Andrea 
Published: February 2019

Abstract
Tumor-specific CD8 T-cells in cancers enter a state of dysfunction characterized by the expression of inhibitory receptors and failure to produce effector cytokines and cytotoxic molecules. Here we identify the nuclear factor, Thymocyte selection-associated HMG box protein, TOX, as a master regulator of tumor-specific T-cell dysfunction. TOX is uniquely expressed in dysfunctional CD8 T-cells from mouse and human tumors but absent in functional T-cells. TOX expression is driven by continuous TCR stimulation and NFAT activity. Forced expression of TOX in functional effector T-cells was sufficient to induce a transcriptional program of dysfunction through the concerted expression of genes encoding numerous inhibitory receptors and dysfunction-associated transcription factors. Notably, TOX-deficient tumor-infiltrating T-cells did not upregulate inhibitory receptors such as PD1, LAG3, CD38, or CD39 and maintained high TCF1 expression. Surprisingly, despite their normal, “non-exhausted” phenotype, TOX-deficient T-cells failed to make effector cytokines, suggesting that loss of effector function in tumor-specific T-cells is uncoupled from inhibitory receptor expression. Furthermore, TOX-deficient T-cells failed to persist in tumors, ultimately undergoing activation-induced cell death. We propose that the TOX-induced transcriptional program of hyporesponsiveness is a physiologic negative feedback mechanism that prevents overstimulation; thus TOX is absolutely required for T-cell survival in the setting of chronic antigen stimulation as in cancers.
Citation Format: Andrew C. Scott, Steven Camara, Peter Lauer, Alexandra Synder, Dmitriy Zamarin, Tyler Walther, Olivier Levy, Michael Glickman, Jonathan Kaye, Mary Philip, Andrea Schietinger. Thymocyte selection-associated HMG box protein TOX is a master regulator of tumor-specific T-cell dysfunction [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 A215.
Abstract A216: Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to checkpoint blockade
Authors: Sen Debattama R. , Miller Brian C. , Abosy Rose Al , Bi Kevin , LaFleur Martin W. , Yates Kathleen B. , Lako Ana , Felt Kristen D. , Naik Girish S. , Manos Michael , Gjini Evisa , Virkud Yamini V. , Hodi Stephen , Rodig Scott J. , Sharpe Arlene H. , Haining W. Nicholas 
Published: February 2019

Abstract
T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T-cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is effective only in a minority of patients. The basis for T-cell dysfunction in the TME, as well as the mechanisms by which anti-PD-1 therapy acts on dysfunctional T-cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models as well as patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T-cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of “stem-like exhausted” T-cells that have a distinct regulatory state. Stem-like exhausted TILs also have critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, stem-like exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Stem-like exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy without reversion of their exhausted epigenetic state. CD8+ T-cells with a stem-like exhausted phenotype can be found in human melanoma samples and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Responsiveness to checkpoint blockade is therefore restricted to a subpopulation of exhausted TILs that retain specific functional properties which enable them to control tumors. Approaches to expand stem-like exhausted CD8+ T-cells in the tumor microenvironment may be an important component of improving checkpoint blockade response.
Citation Format: Debattama R. Sen, Brian C. Miller, Rose Al Abosy, Kevin Bi, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen D. Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Yamini V. Virkud, Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to 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 A216.
Abstract B025: Multiplex three-dimensional mapping of mRNA and protein in the tumor microenvironment
Authors: Lee Steve Seung-Young , Scholten David , Bindokas Vytautas P. , Kron Stephen 
Published: February 2019

Abstract
Detecting oncogenic protein-coding messenger RNA (mRNA) in tumor tissues is a key assay for accurate cancer diagnosis. Along with cancer protein biomarker analysis, mRNA identification is critical for matching the appropriate treatment to individual patients. Likewise, cytokine mRNA localization in on-treatment biopsies enables evaluation of the antitumor response to immunotherapy by identifying the types and functional states of lymphocytes, for example distinguishing activated cytotoxic T-cells from naive T-cells. To assess mRNA localization, a biopsy is typically formalin fixed and paraffin embedded (FFPE), thin sections are cut, and then are stained for mRNA by chromogenic In situ hybridization (CISH). Analyzing samples by mRNA CISH typically takes a few days and requires considerable technical expertise. Recent progress in multiplexed fluorescence In situ hybridization (FISH) has enabled simultaneous analysis of multiple mRNA types in a single tissue section. Nonetheless, even if fully characterized, individual tissue sections cannot adequately represent the complex three-dimensional (3D) architecture of the tumor microenvironment. There remains a pressing need for a rapid sample-to-answer technology for multiplex 3D imaging of mRNA at sub-cellular resolution that is able to fully characterize the tumor microenvironment in intact biopsy tissues for cancer diagnosis and immunotherapeutic response analysis. To address these challenges, we have adapted Transparent Tissue Tomography (T3), a simple and fast tissue clearing and multiplex 3D imaging method, to analyze mRNA distribution in the tumor microenvironment. With T3, oncogenic and immunoregulatory cytokine mRNAs are readily localized in the context of cell types and other features in murine, patient derived xenograft (PDX), and head and neck tumors. This work establishes T3 as a tool for a quantitative, 3D spatial analysis of mRNA and protein distribution in the tumor microenvironment.
Citation Format: Steve Seung-Young Lee, David Scholten, Vytautas P. Bindokas, Stephen Kron. Multiplex three-dimensional mapping of mRNA and protein in the tumor microenvironment [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 B025.
Abstract B039: Peptide-MHC-directed expansion of multifunctional antigen-responsive T-cells
Authors: Rafa Vibeke Mindahl , Bodenhöfer Mona , Bentzen Amalie Kai , Tamhane Tripti , Donia Marco , Svane Inge Marie Stentoft , Jakobsen Søren Nyboe , Schmess Christian , Hadrup Sine Reker 
Published: February 2019

Abstract
Functional properties and antigen specificity of expanded T-cells are crucial for the efficacy of adoptive cell transfer-based therapies in cancer. Most current strategies involve nonspecific expansion of bulk tumor-infiltrating lymphocytes, often providing growth preference to co-infiltrated virus specific T-cells and driving an exhausted phenotype of the expanded T-cell product.A potential way to resolve this challenge, is the use of artificial antigen-presenting scaffolds providing both an antigen specific stimulation through peptide-MHC interaction and additional the required co-stimulatory and growth signals through associated stimulatory molecules and cytokines. We have designed such antigen-presenting scaffolds; build on a dextran-polysaccharide, carrying both peptide-MHC and relevant stimulatory molecules. The artificial antigen-presenting scaffolds interacts specifically with T-cells based on recognition of the peptide-MHC molecule and effectively expand and functionally stimulate specific T-cells in a peptide-MHC-directed fashion, while leaving all other T-cell specificities untouched. Results from in vitro experiments have showed that antigen specific CD8 T-cells stimulated with these artificial antigen-presenting scaffolds express a less differentiated phenotype and low PD-1 expression, associated with high proliferation potential and enhanced antitumor effect in vivo. Furthermore, this expansion strategy provides a high frequency of multifunctional antigen specific CD8 T-cells expressing IFN-γ, TNF-α, and CD107a upon target recognition and provide improved cancer cell killing over IL2-driven expansion of tumor-infiltrating lymphocytes. Furthermore, the current strategy allows for simultaneous expansion of numerous different T-cell populations, required to generate T-cell products with broad recognition profiles based on the personal cancer-antigen and mutational profile. All of these characteristics are of significant importance for in vivo tumor cell killing following adoptive transfer of expanded T-cell products. Thus, the present strategy represents an optimized method for expansion of cancer-restricted T-cells for adoptive cell therapy.
Citation Format: Vibeke Mindahl Rafa, Mona Bodenhöfer, Amalie Kai Bentzen, Tripti Tamhane, Marco Donia, Inge Marie Stentoft Svane, Søren Nyboe Jakobsen, Christian Schmess, Sine Reker Hadrup. Peptide-MHC-directed expansion of multifunctional antigen-responsive T-cells [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 B039.
Abstract B045: Antigen-free cancer vaccine to treat poorly immunogenic tumors
Authors: Sobral Miguel C. , Wang Hua , Najibi Alexander J. , Li Aileen , Verbeke Catia S. , Mooney David J. 
Published: February 2019

Abstract
Certain chemotherapeutic drugs can elicit immunogenic death of tumor cells and enhance antitumor immune responses. Here we explore whether immunogenic chemotherapy can be utilized for the development of antigen-free cancer vaccines, by combining it with peritumorally injected biomaterial scaffolds that recruit dendritic cells (DCs) for subsequent antigen presentation and T-cell priming. Pore-forming alginate gels containing granulocyte-macrophage colony-stimulating factor (GM-CSF) and a doxorubicin-iRGD conjugate were found to efficiently induce the apoptosis of 4T1 triple-negative breast cancer cells in vivo, while recruiting large numbers of DCs. The co-encapsulation of CpG oligodeoxynucleotides in the gel significantly enhanced the immunogenic death of 4T1 cells, increased systemic tumor-specific CD8+ T-cells and tumoral infiltration of CD8+ T-cells, repolarized tumor-associated macrophages towards an inflammatory M1-like phenotype, and resulted in significantly improved antitumor efficacy. This in situ antigen-free gel vaccine shows promise for the treatment of poorly immunogenic tumors, and more broadly, may serve as a facile platform to enable in situ personalized cancer vaccination without requiring identification of tumor-specific antigens and manufacturing of personalized vaccines.
Citation Format: Miguel C. Sobral, Hua Wang, Alexander J. Najibi, Aileen Li, Catia S. Verbeke, David J. Mooney. Antigen-free cancer vaccine to treat poorly immunogenic 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 B045.