bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A087: Quantifying the landscape of immunostimulatory tumoral RNA
Authors: Solovyov Alexander , Tanne Antoine , Muniz Luciana , Cocco Simona , Monasson Remi , Levine Arnold , Ting David T. , Bhardwaj Nina , Greenbaum Benjamin 
Published: November 2016

Abstract
Recent studies demonstrate an unexpected connection between aberrant transcription of noncoding RNA in tumors and innate immune system activation in the tumor microenvironment. Such RNA is often of unknown function and may consist of typically silenced interspersed elements, satellite repeats, and endogenous retroviruses. For instance, satellite RNA from the pericentromere (particularly HSATII) is abundantly transcribed in several solid tumors - such as pancreatic ductal adenocarcinoma - yet it is virtually silent in normal tissue. The genomic DNA repetitive regions this RNA is transcribed from frequently expand during tumorigenesis. Using novel quantitative methods, we have shown that a set of such repetitive elements, abundantly expressed in tumors, display sequence patterns typically associated with viruses. We therefore predicted they are immunogenic, particularly HSATII. In a novel, theory-experiment collaboration between the laboratories of Professors Benjamin Greenbaum and Nina Bhardwaj, the most significant set of these RNA have been validated as immunostimulatory (HSATII and murine GSAT), capable of activating antigen presenting cells - HSATII stimulated production of IL-6, IL-12 and TNFalpha (Tanne, et al., PNAS, 2015).
At the same time a set of recent papers has shown that ERV transcription may be a predictor of immunotherapy response in melanoma. Hence, it is critical to profile key immunostimulatory endogenous RNA in the tumor microenviroment, understand which immune pathways different sets of such RNA activate, and assess the link between the specific pathways activated, prognosis, and immunotherapy. We further profile the landscape of activation and expression for endogenous elements. We have currently demonstrated a key set of noncoding RNAs preferentially expressed in cancer cells have sequence features that are immunostimulatory in humans, and have characterized the range and breadth of the expression of such elements in several solid tumors. We present several new results on the topic and the potential consequences of the aberrant expression of endogenous RNA that mimic pathogen features in cancer.
Citation Format: Alexander Solovyov, Antoine Tanne, Luciana Muniz, Simona Cocco, Remi Monasson, Arnold Levine, David T. Ting, Nina Bhardwaj, Benjamin Greenbaum. Quantifying the landscape of immunostimulatory tumoral RNA [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A087.
Abstract A089: Multiparametric immunofluorescence analysis of the tumor microenvironment using CODEX
Authors: Kennedy-Darling Julia , Nolan Garry P. , Goltsev Yury , Samusik Nikolay 
Published: November 2016

Abstract
The tumor microenvironment plays a critical role in cancer progression and has implications for the efficacy of various cancer immunotherapy treatment options. Immune infiltrates within the tumor microenvironment can correlate with both positive and negative outcomes, depending upon the both the type of cancer as well as infiltrating immune cell(s). These analyses are typically performed using standard immunofluorescence and immunohistochemistry assays where no more than four simultaneous parameters can be visualized on the same tissue. Unfortunately, these tools cannot fully characterize the complexity of the tumor microenvironment due to the inherent limitations of fluorophore spectral overlap. In order to identify each type of immune and tumor cell within a single tissue, at least 40 parameters need to be measured simultaneously. We have developed a multiparametric immunofluorescence technology, entitled CODEX (Co-Detection by IndEXing), which utilizes unique DNA tags as a means of iteratively measuring more than 40 parameters within the same tissue. More than 40 human antibodies have been validated using this approach, including numerous immune markers, checkpoint ligands, tumor markers and cellular activity markers. We are currently analyzing tissue sample from patients with lung cancer. By measuring nearly 50 simultaneous markers within the same tissue, CODEX has the potential to greatly enhance our knowledge of the tumor microenvironment and more accurately define immune infiltrates at the single-cell level.
Citation Format: Julia Kennedy-Darling, Garry P. Nolan, Yury Goltsev, Nikolay Samusik. Multiparametric immunofluorescence analysis of the tumor microenvironment using CODEX [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A089.
Abstract A093: Impact of antigen affinity on T cell dysfunction in solid tumors
Authors: Shakiba Mojdeh , Philip Mary , Schietinger Andrea 
Published: November 2016

Abstract
Although tumor-specific CD8 T cells are found in human solid tumors, cancers progress, indicating that these T cells are dysfunctional. When naïve CD8 T cells encounter antigen in an inflammatory context (e.g. acute infection), a cell-intrinsic program is initiated that drives T cells to expand, produce effector cytokines, and differentiate into effector and memory T cells. In contrast, dysfunctional CD8 T cells in solid tumors express high levels of inhibitory receptors and fail to execute effector functions; however, the regulatory mechanisms underlying tumor-specific T cell dysfunction remain poorly defined. T cell-mediated immune responses are triggered by T cell receptor (TCR) binding to peptide-major histocompatibility complex (pMHC) on the surface of antigen presenting cells. The affinity of TCR:pMHC interaction is a critical determinant of CD8 T cell expansion and effector function in acute infections; while both low- and high-affinity antigens can activate naïve antigen-specific CD8 T cells, T cells with high-affinity TCR:pMHC interactions generally show superior effector function. However, little is known about how tumor antigen affinity impacts the activation of T cells, the induction of T cell dysfunction in progressing tumors, and T cell susceptibility to immunotherapeutic reprogramming. To investigate the role of TCR:pMHC affinity in T cell differentiation in progressing tumors, we generated tumor cell lines expressing altered peptide ligands (APL) derived from SV40 large T antigen epitope I (SV40-I). These APLs are recognized by SV40-I-specific transgenic CD8 T cells (TCRSV40-I) with varying functional avidity. We found that tumor-infiltrating TCRSV40-I encountering low- and high-affinity tumor antigens were equally activated and displayed similar expression levels of inhibitory receptors, such as PD1 and Lag3, suggesting that even very weak TCR ligations can induce a typical “exhaustion” phenotype. Strikingly, while high-affinity TCR:pMHC interactions led to complete loss of interferon gamma and tumor necrosis factor alpha production, T cells with low-affinity interactions remained functional and capable of producing high levels of these effector cytokines suggesting that contrary to our expectations, tumor-specific T cells with high-affinity TCR:pMHC interactions enter a profound state of dysfunction. Future experiments will test the impact of tumor antigen affinity on the efficacy of therapeutic reprogramming including checkpoint blockade, which will have important implications for immunotherapy.
Citation Format: Mojdeh Shakiba, Mary Philip, Andrea Schietinger. Impact of antigen affinity on T cell dysfunction in solid tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A093.
Abstract A109: Immune profiling of tumor infiltrating lymphocyte subsets, myeloid cells and HPV status of HNSCC biopsies using multiplex immunofluorescence
Authors: Levin Matt , Lingen Mark , Schwartz David , Snyder Helen 
Published: November 2016

Abstract
Head and neck squamous cell carcinoma (HNSCC) has both human papilloma virus (HPV) positive and negative etiologies. It is one of the growing number of tumors for which an anti-tumor immune response is implicated to play a role in the course of disease as shown by responsiveness to immune-modulation using PD-1/PD-L1 inhibitors. Profiling of the tumor microenvironment including specific infiltrating lymphocyte subsets, antigen presenting cells, expression of regulatory molecules on both tumor and immune cells, and spatial relationships between cells could lead to predictive signatures for responsiveness to both conventional and immune modulatory therapies. However, such profiling has previously been hindered by the need to identify such cells “in-situ” in tissue sections using multiple markers per cell, and limitations in available technology. The current study demonstrates Cell IDx's novel UltraPlex technology, based on a simple two step protocol using hapten labeled primary antibody cocktails followed by fluor labeled anti-hapten secondary cocktails, allowing simultaneous detection of 4 markers on the same cell. Analysis of HNSCC positive and negative tissue microarrays combining UltraPlex detection of multiple markers per cell together with serial sections stained with individual phenotyping panels demonstrates a powerful technique for 12-16 plex analysis. This permits HPV status determination, immune subset profiling, quantitative marker expression, relative cellular localization and potential for correlative signature determination associated with disease outcome and response to treatment.
Citation Format: Matt Levin, Mark Lingen, David Schwartz, Helen Snyder. Immune profiling of tumor infiltrating lymphocyte subsets, myeloid cells and HPV status of HNSCC biopsies using multiplex immunofluorescence [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A109.
Abstract A112: Manipulating tumor microenvironment for immunotherapy
Authors: Tang Haidong , Qiu Xiangyan , Wang Yang , Fu Yang-Xin 
Published: November 2016

Abstract
An established tumor is a complex tissue composed of tumor cells, stromal cells, inflammatory cells, vasculatures, and extracellular matrices, all of which are defined together as the tumor microenvironment. Successful tumor control by immunotherapy requires activation of the immune system, expansion of the effector cells, infiltration of activated effector cells to the tumor tissue, and destruction of the tumor cells. Our previous studies have showed that anti-tumor effect of current tumor immunotherapies, such as checkpoint blockade, relies on a significant number of spontaneous tumor infiltrating lymphocytes. However, established tumors often inhibit peripheral lymphocytes entering tumor tissues for tumor destruction. Inflammatory mediators, especially cytokines, chemokines, and adhesion molecules, play important roles in the recruitment and activation of various types of innate and adaptive immune cells. As a proof-of-concept study, we targeted tumor tissues with LIGHT, a member of the tumor necrosis factor super family. Our data suggested that targeting tumor with LIGHT is able to induce the production of several cytokines/chemokines, which recruit T cells into tumor microenvironment, leading to tumor regression. Furthermore, combination therapy with LIGHT is able to overcome tumor resistance to checkpoint blockade. Thus, these data suggested that manipulating tumor microenvironment with cytokines/chemokines that are able to recruit effector cells represents a promising strategy for tumor immunotherapy. To better understand the role of individual cytokine/chemokine, we utilized chemokine array to systemically analyze tumor microenvironments. By comparing chemokine profiles from immunotherapy-sensitive and -insensitive tumors, we found a significant difference which might be responsible for their sensitivity to immunotherapies. Sensitive tumor is characterized with a higher level of chemokines associated with lymphoid cell trafficking, such as CXCL9 and CCL22. In contrast, insensitive tumor is characterized by a higher levels of chemokines associated with myeloid cell, such as MCP-1 and CCL11. The contributions and their therapeutic potentials of these cytokines/chemokines will be studied in the next step.
Citation Format: Haidong Tang, Xiangyan Qiu, Yang Wang, Yang-Xin Fu. Manipulating tumor microenvironment for immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A112.
Abstract A118: CD103+/PD-1+ T-cells identify a subset of triple-negative breast cancer eligible for targeted checkpoint inhibition
Authors: Bottai Giulia , Roncalli Massimo , Santarpia Libero 
Published: November 2016

Abstract
The presence of tumor-infiltrating lymphocytes (TILs) is a prognostic factor in triple-negative breast cancer (TNBC). Specifically, cytotoxic CD8+ cells are associated with favorable outcome in TNBC. Recently, the integrin CD103 has been suggested as a potential prognostic marker in breast cancer. In this study, we aimed to evaluate the functional status and clinical relevance of CD8+ and CD103+ TILs in TNBC.
A retrospective cohort of 210 formalin-fixed, paraffin-embedded tissues from patients with primary invasive ductal TNBC was assessed for the presence of CD8, CD103 and the checkpoint receptor PD-1 by immunohistochemistry assay. Whole tumor slides were assessed. Cases where ≥5% of TILs expressed CD103 or PD-1 were considered positive. Statistical analyses were performed using Spearman's correlation, Kaplan-Meier and Cox regression analyses.
We found that CD103+ cells mostly co-expressed the CD8 marker, and were preferentially distributed within tumor epithelium. No consistent correlation was found between the presence of CD103+ lymphocytes and the expression of its ligand E-cadherin by TNBC cells (rs = 0.365). CD8+ lymphocytes were consistently associated with better relapse-free survival (RFS) and overall survival (OS) in both univariate (HR = 0.61; P = 1.06E-02 for RFS; HR = 0.59; P = 1.93E-02 for OS) and multivariate analysis (HR = 0.65; P = 2.45E-02 for RFS; HR = 0.63; P = 3.96E-02 for OS). The presence of CD103+ lymphocytes significantly correlated with prolonged RFS and OS in univariate analysis only (HR = 0.82; P = 4.12E-02 for RFS; HR = 0.85; P = 4.93E-02 for OS), and a trend for longer RFS was also observed in univariate analysis for PD-1 (HR = 0.71; P = 5.22E-02). Interestingly, a subset of TNBC showed co-expression of CD103+/PD-1+ in lymphocytes localized to the intraepithelial areas of the tumor.
The expression of CD103 on CD8+ T cells in direct contact with cancer cells may identify a subpopulation of cells with potent cytolytic activity. The interaction between CD103+ cytotoxic lymphocytes and TNBC cells is mediated by different mechanisms rather than the binding to E-cadherin. Even though CD103 has a role in mediating an effective anti-tumor immune response, its presence alone may not be sufficient to impact the outcome of TNBC patients. Immunomodulatory therapies may be useful to boost the anti-tumor activity of potentially quiescent CD103+/PD-1+ cells in a subgroup of TNBC patients.
Citation Format: Giulia Bottai, Massimo Roncalli, Libero Santarpia. CD103+/PD-1+ T-cells identify a subset of triple-negative breast cancer eligible for targeted checkpoint inhibition [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A118.
Abstract A136: p16INK4a status of primary tumor modulates local immune response in vulvar squamous cell carcinoma
Authors: Sznurkowski Jacek J. , Zawrocki Anton 
Published: November 2016

Abstract
Background: The p16INK4a is not a surrogate marker for high-risk human papilloma virus genotypes (hr)HPV-DNA) and was suggested to indicate better prognosis of vulvar squamous carcinoma (vSCC). Our recent study confirmed substantial mismatch between p16ink4a and (hr)HPV-status as well as prognostic significance exclusively for p16INK4a-overexpression in cohort of 85 patients. Aim: To compare the infiltration of tumor infiltrating lymphocytes (TILs) and to assess their prognostic significance in cases having tumors with opposed p16INK4a and (hr)HPV-status.
Methods: TILs (CD8+, CD4+, FOXP3+, CD68+, CD56+ and GzB+ cells) were calculated in 85 vSCCs with previously defined p16INK4a and (hr)HPV-status. Number of intraepithelial (IE) TIL-subtypes were compared between tumors with different p16INK4a and (hr)HPV-status separately. Survival analyses included the Kaplan-Meier method, log-rank test and Cox proportional hazards model.
Results: p16INK4a-negative tumors were infiltrated more intensely by CD8+, CD4+ and GZB+ cells than p16INK4a-positive vSCCs (p = 0.032, p = 0.016 and p = 0.007 respectively). (hr)HPV-status did not impact the infiltration of TILs. Median follow up was 89.20 months (range 1.7-189.5). High (IE)CD4+ infiltrates were prognostic in general cohort and in p16INK4a-positive cases (p = 0.032 and p = 0.039 respectively). High (IE)CD56+ infiltrates were correlated with prognosis in p16INK4a-positive and (hr)HPV-positive cases (p = 0.013 and p = 0.0458 respectively) while high (IE)CD68+ infiltrates were inversely correlated with survival in cases with p16INK4a-negative and (hr)HPV-negative tumors (p = 0.018 and p = 0.0441 respectively).
Conclusion: p16INK4a-status modulates local immune surveillance as represented by TILs. Immunologic effects contributing to clinical outcome might depend on p16INK4a-overexpression.
Citation Format: Jacek J. Sznurkowski, Anton Zawrocki. p16INK4a status of primary tumor modulates local immune response in vulvar squamous cell carcinoma [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A136.
Abstract A145: The prognostic significance of programmed cell death-ligand 1 expression in pulmonary squamous cell carcinoma
Authors: Hung Jung-Jyh , Wu Yu-Chung , Hsu Wen-Hu 
Published: November 2016

Abstract
Introduction: The programmed cell death-ligand 1 (PD-L1) pathway plays an important role in maintaining immune homeostasis. PD-L1 pathway may also protect tumor from attack of cytotoxic T cells. The prognostic significance of PD-L1 expression in pulmonary squamous cell carcinoma has not been well demonstrated.
Methods: A total of 98 patients with resected pulmonary squamous cell carcinoma were included in the study. PD-L1 expression was determined by immunohistochemistry in tumor specimens. Relationship between PD-L1 expression and clinicopathological variables was investigated. The prognostic value of PD-L1 expression in overall survival (OS) and probability of freedom from recurrence [FFR] was also demonstrated in the study.
Results: PD-L1 expression was identified in 72 (73.5%) of the 98 lung tumor samples. PD-L1 expression was significantly associated with advanced stage (P = 0.045). PD-L1 expression (hazard ratio, 0.347; 95% confidence interval, 0.148 to 0.814; P = 0.015) was a significant prognostic factor for better OS in multivariate analysis. For patients with stage I/II lung squamous cell carcinoma, PD-L1 expression was a significant prognostic factor for better OS (HR, 0.299; 95% CI, 0.114 to 0.786; P = 0.014) and probability of FFR (HR, 0.346; 95% CI, 0.143 to 0.836; P = 0.025) in multivariate analysis.
Conclusions: PD-L1 expression was significantly associated with advanced stage in pulmonary squamous cell carcinoma. PD-L1 expression was a significant prognostic factor for better OS in patients with pulmonary squamous cell carcinoma, and also a significant prognostic factor for better probability of FFR in those with early-stage pulmonary squamous cell carcinoma.
Citation Format: Jung-Jyh Hung, Yu-Chung Wu, Wen-Hu Hsu. The prognostic significance of programmed cell death-ligand 1 expression in pulmonary squamous cell carcinoma [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A145.
Abstract A148: Control of regulatory T (Treg) cell function by protein kinase C-eta (PKCη): A novel target for cancer immunotherapy
Authors: Pedros Christophe , Kong Kok-Fai , Altman Amnon 
Published: November 2016

Abstract
Modulating regulatory T cell (Treg) function to promote anti-tumor immunity is a desirable strategy for cancer immunotherapy. Blockade of checkpoint molecules, CTLA-4 and PD-1, has shown clinical efficacy in advanced metastatic melanoma and other malignancies. We recently reported that Treg stimulation induced the recruitment of protein kinase C-eta (PKCη), together with the GIT-PAK-PIX signaling complex that mediates focal adhesion disassembly, to CTLA-4, an inhibitory receptor highly expressed on Foxp3+ Tregs, which is important for Treg suppression. This resulted in PKCη localization in the Treg immunological synapse. These events promoted and were obligatory for Treg-mediated contact-dependent suppression, including suppression of tumor immunity via a mechanism likely involving depletion of costimulatory CD80/86 ligands from APCs (Nat Immunol. 2014;15:465-72). PKCη-deficient (PKCη−/−) Tregs were defective in the suppression of anti-tumor immunity against B16 melanoma and the slow growing prostate adenocarcinoma TRAMP-C1 but, surprisingly, retained the ability to inhibit experimental autoimmune colitis, a disease that often occurs in cancer patients treated with checkpoint inhibitors. Moreover, PKCη loss in Treg cells increased the number of intratumoral CD4+ and CD8+ effector T cells without affecting Treg numbers, resulting in a significant increase of the intratumoral Teff:Treg cell ratio, a parameter considered to predict a better clinical outcome. Impaired activation of the GIT-PAK-PIX complex and the resulting defect in CD80/86 depletion are likely responsible for the defective suppressive activity of PKCη−/- Tregs. These findings establish the novel CTLA-4-PKCη signaling pathway as critical for suppressing tumor immunity, and implicate it as an attractive cancer immunotherapy target.
Citation Format: Christophe Pedros, Kok-Fai Kong, Amnon Altman. Control of regulatory T (Treg) cell function by protein kinase C-eta (PKCη): A novel target for cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A148.