bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A58: JAK1 deficiency as a novel mechanism of tumor immune escape in uterine cancer
Authors: Ren Yuan , Zhang Yonghong , Liu Richard Z. , Fenstermacher David A. , Wright Kenneth L. , Teer Jamie K. , Wu Jie 
Published: October 2015

Abstract
Recognition of MHC class I antigens on the surface of tumor cells is an essential process in the effector phase of CD8+ cytotoxic T lymphocyte (CTL)-mediated anti-tumor response. Presentation of MHC class I antigens on tumor cells is regulated by the JAK1/JAK2-mediated interferon-γ signaling pathway. We analyzed the targeted exome sequencing data of 3,274 human tumors from 48 different tissues in the Total Cancer Care (TCC) tumor bank and found JAK1 truncating mutations in 36 of 635 gynecologic tumors. The highest JAK1 truncating mutation rate (9.5%) was found in endometrial cancer. These truncating mutations result in the loss of the JAK1 protein tyrosine kinase (PTK) domain that is located in the C-terminal region. JAK1 truncating mutations in cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE) databank also occur most often in endometrial cancer cells. Analysis of mutation sites identified three mutation hot spots. Re-sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed JAK1 mutations and revealed that these JAK1 mutations are somatic. Besides JAK1, recurrent JAK2 loss-of-function (LOF) mutations were also found in TCC tumors but at lower rates. Similar to JAK1, the highest rate of LOF JAK2 mutations was found in endometrial/uterine cancer. No JAK1 or JAK2 truncating mutation was identified in 130 samples from hematological malignancies. Functional assays showed that JAK1 deficient cancer cells were defective in interferon-γ-induced expression of tumor antigen processing machinery proteins LMP2 and TAP1 and cell surface expression of HLA molecules. These data identify recurrent JAK1 deficiency in endometrial cancer that impairs tumor antigen presentation by the MHC class I complex to CTLs. While PTKs have been perceived mostly as oncogenes and PTK inhibitors, including JAK inhibitors, have been developed for cancer therapy, our findings suggest that JAK1 is a novel tumor suppressor and that LOF JAK1 mutations allow tumor immune escape. Our findings also raise caution about the use of JAK inhibitors as therapeutic agents in solid tumors.
Citation Format: Yuan Ren, Yonghong Zhang, Richard Z. Liu, David A. Fenstermacher, Kenneth L. Wright, Jamie K. Teer, Jie Wu. JAK1 deficiency as a novel mechanism of tumor immune escape in uterine cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A58.
Abstract A63: The role of DARC in the immunological tumor microenvironment of breast cancer
Authors: Davis Melissa B. , Monteil Michele , Hire Rupali , Howerth Elizabeth W. 
Published: October 2015

Abstract
The Duffy Antigen Receptor for Chemokines (DARC or ACKR1) gene regulates circulating levels of inflammatory chemokines and major alleles of the gene are associated with a myriad of clinical outcomes. There are two unique isoforms of DARC which are expressed from distinct separate promoters, but little is known about the expression or regulation of these isoforms. Using quantitative RT-PCR and Immunohistochemical studies of lymphoblastic cells from relevant ancestry groups, we recently found that a DARC polymorphism, the Duffy Null (Fy-) allele found almost exclusively in African ancestry groups, is associated with altered regulation of these isoforms. Our data indicates that people of African ancestry who carry the Fy- allele will have an altered expression pattern of DARC isoforms. Thusly, we investigated whether the Fy- allele is associated with distinct recruitment of monocytes to breast tumor epithelia, regulated by DARC modulated chemokines. This may translate into a suite of distinct inflammatory responses correlated with specific chemokine action and may explain the disparate clinical outcomes of breast cancer in this population.
Citation Format: Melissa B. Davis, Michele Monteil, Rupali Hire, Elizabeth W. Howerth. The role of DARC in the immunological tumor microenvironment of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A63.
Abstract A64: Chronic allergic contact dermatitis, A potent tumor promoter of Marjolin's ulcer
Authors: Demehri Shadmehr , Cunningham Trevor J. , Hurst Eva A. , Schaffer Andras , Sheinbein David M. , Yokoyama Wayne M. 
Published: October 2015

Abstract
Allergic contact dermatitis (ACD) is a well-recognized adverse event associated with implantable medical devices that contain allergenic materials like nickel. However, other cutaneous consequences of such chronic exposures are not well understood. Herein, we report a clinical case of Marjolin's ulcer, an invasive squamous cell carcinoma (SCC) developing at the site of chronic inflammation from a previously unreported cause: chronic ACD caused by an orthopedic implant. To determine whether chronic ACD promotes skin carcinogenesis, we utilized a standard murine model of contact hypersensitivity. The chronic application of 1-Fluoro-2,4-dinitrobenzene (DNFB) to carcinogen-treated skin led to the development of papillomas and aggressive SCC. The DNFB-driven chronic ACD was marked by type 2 inflammation that mediated the skin carcinogenesis. Importantly, we found similar tumor-promoting inflammation surrounding the SCC in our patient. Our findings demonstrate that chronic ACD caused by constant exposure to an allergen can promote tumorigenesis at skin sites with pre-existing cancer-initiated cells. This has great implication for the monitoring of implantable devices that are placed in the proximity of the skin and highlights the importance of patch testing prior to the placement of such devices.
Citation Format: Shadmehr Demehri, Trevor J. Cunningham, Eva A. Hurst, Andras Schaffer, David M. Sheinbein, Wayne M. Yokoyama. Chronic allergic contact dermatitis, A potent tumor promoter of Marjolin's ulcer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A64.
Abstract B07: Characterization of T-cell therapy enhancing oncolytic adenoviruses with human cytokine expression
Authors: Havunen Riikka , Parviainen Suvi , Siurala Mikko , Hemminki Akseli 
Published: October 2015

Abstract
Adenovirus vectors are the most commonly used gene therapy vectors in clinical trials. Administrated systemically or intratumorally the virus is capable of inducing immune responses against the tumor per se, but this effect can also be amplified by arming the viruses with immune system stimulating factors. Moreover, we have discovered that adenoviruses enhance adoptive T-cell therapy in a potent manner. Our previous data also shows that the most promising factors to stimulate immune system are interleukin (IL) -2 and Tumor Necrosis Factor alpha (TNFα). IL-2 is a commonly used cytokine in treating malignant melanoma and renal cell carcinoma. However, systemic IL-2 can in some cases lead to severe side effects. Like IL-2, TNFα activates immune cells, but it is also known for its anti-tumor properties and it is for example capable of promoting tumor cell death by apoptosis and necrosis. Arming oncolytic viruses with cytokines results in long lasting, high level expression locally but low level systemically. Currently, we are developing oncolytic adenoviruses with expression of one or both of the above mentioned human cytokines. The viruses have an Ad5/3 chimera that is generated through replacement of the Ad5 fiber knob with the Ad3 knob while the Ad5 shaft and tail are retained. The chimera has proven to have an improved cancer cell transduction as well as antitumor efficacy. In addition, the viral genome has an E2F promoter and a 24-basepair deletion at the E1A domain, which makes it selective to retinoblastoma protein defective cells (most tumor cells). The viral particles are produced in A549 lung adenocarcinoma cell line. The genomes are sequenced and the functionality of the viruses and the cytokines proven with various methods. The secretion of cytokines is tested with ELISA and by using indicator cell lines. The functionality of the viruses is studied by infecting different cells lines with variable amount of viral particles and measuring the proportion of surviving cells with MTS-assay. Our data proves oncolytic and cytokine production capability of Ad5/3-E2F-D24-hTNFα/hIL2 adenoviruses. The results indicate that these viruses can be used in further investigations in vivo.
Citation Format: Riikka Havunen, Suvi Parviainen, Mikko Siurala, Akseli Hemminki. Characterization of T-cell therapy enhancing oncolytic adenoviruses with human cytokine expression. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B07.
Abstract B13: Prostate cancer immunotherapy development using tumor-specific CAR design
Authors: Prima Victor , Kusmartsev Sergei , Vieweg Johannes 
Published: October 2015

Abstract
Prostate cancer that has progressed to metastatic disease remains largely untreatable. One of the most promising modalities for treatment of advanced cancer is immunotherapy based on adoptive transfer of T lymphocytes. It was demonstrated that T lymphocytes expressing tumor-specific chimeric artificial receptor (CAR) exert potent anti-tumor activity upon adoptive transfer into tumor-bearing host. Recent studies identified Prostate-specific membrane antigen (PSMA) and ligands for NK cell –activating receptors (e.g. NKG2D ligands) as the targets primarily expressed on tumor cells but absent on most normal tissues. We generated two sets of chimeric DNA constructs: CAR-PSMA and CAR-NKG2D, that can be used for transduction of human T cells. Both of them consist of an antigen-recognizing domain bound to the transmembrane and intracellular domains of various signal-transducing and/or cell-activating molecules and a signaling molecule. Extracellular antigen-recognizing domain of CAR-PSMA consists of single chain anti-PSMA antibody (scFv) while in another construct set it is human NKG2D receptor. Intracellular CD3 ξ-chain functions as a signaling molecule triggering T-cell activation. Co-stimulatory proteins CD28, CD40L or OX40L which can compensate for the lack of co-stimulation from the target tumor cell are either fused to CD3 ξ-chain as intracellular domains or are expressed on cell surface from bi-cistronic constructs.
Upon transduction of human T cells with these constructs, transduced cells presented surface expression of the chimeric scFv anti-PSMA or NKG2D, respectively. In vitro experiments demonstrated specific binding activity and cytotoxicity of human T lymphocytes expressing anti-PSMA or NKG2D CARs against prostate cancer cells which creates the basis for a viable prostate cancer immunotherapy development.
*VP and SK contributed equally to the project.
Citation Format: Victor Prima, Sergei Kusmartsev, Johannes Vieweg. Prostate cancer immunotherapy development using tumor-specific CAR design. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B13.
Abstract B22: A chimeric antigen receptor (CARs) based upon a killer immunoglobulin-like receptor (KIR) triggers robust cytotoxic activity in solid tumors
Authors: Wang Enxiu , Wang Liang-Chuan , Tsai Ching-Yi , Bhoj Vijay , Albelda Steven , Moon Edmund , Milone Michael C. 
Published: October 2015

Abstract
Chimeric antigen receptors (CARs) based upon a single chimeric molecule bearing an antigen binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors CD28 or 4-1BB provide a potent method for engineering T cell cytotoxicity towards tumors. We describe a simple chimeric multichain receptor based upon a killer immunoglobulin-like receptors (KIRs) normally expressed by natural killer (NK) cells and T cells. Constructed by fusing a single chain variable fragment (scFv) to the transmembrane and cytoplasmic domain of a KIR, we show that a KIR-based CAR targeting mesothelin (SS1-KIR) triggers antigen-specific cytotoxic activity and cytokine production that is comparable to CD3ζ-based CARs with antigen-induced proliferation that is independent of additional costimulation. Using a xenograft model of mesothelioma resistant to T cell immunotherapy, we further demonstrate that a KIR-based CAR targeting mesothelin exhibits more potent anti-tumor activity compared with T cells bearing mesothelin-specific CD3ζ-based CARs with costimulation despite in vivo persistence of the latter CAR-modified T cells. Evaluation of tumor infiltrating lymphocytes demonstrate that KIR-based CAR+ T cells show resistance to acquired hypofunction within the tumor microenivornment compared with CD3ζ-based CARs with costimulatory receptor domains. The ability of a KIR-based CAR to induce regression of a tumor in which second generation CD3ζ-based CARs show limited activity supports the future clinical evaluation of a KIR-based CAR in mesothelioma and other tumors.
Citation Format: Enxiu Wang, Liang-Chuan Wang, Ching-Yi Tsai, Vijay Bhoj, Steven Albelda, Edmund Moon, Michael C. Milone. A chimeric antigen receptor (CARs) based upon a killer immunoglobulin-like receptor (KIR) triggers robust cytotoxic activity in solid tumors. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B22.
Abstract B33: Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines
Authors: Lee Sung Yong , Shim JaeJeong , Ho Kang Kyung , Lee Kye Young , Hung Chien-Fu , Wu T.-C. 
Published: October 2015

Abstract
Endoplasmic reticulum stress has a profound effect on cancer cell proliferation and survival, and also has the capacity to activate cells of the adaptive immune system. Multimodality treatments that combine conventional cancer therapies with antigen-specific immunotherapy have emerged as promising approaches for the control of cancer. However, it is not well known whether ER stress inducing agents can influence the efficacy of tumor antigen targeted vaccines. We used previously developed therapeutic human papillomavirus (HPV) DNA vaccines encoding calreticulin (CRT) linked to HPV-16 E7 antigen (CRT/E7) vaccine and ER stress inducing agent, 3-bromopyruvate in a preclinical model for its potential to enhance E7-specific CD8+ T cell immune responses as well as antitumor effects against E7-expressing tumor (TC-1 cells). In vitro assay, luciferase-expressing TC-1 tumor cells were treated with 3-bromopyruvate. E7-specific CD8+ T cells were added to evaluate the cytotoxicity. The degree of cytotoxic T lymphocytes-mediated killing of the tumor cells was measured with the IVIS Luminescence Imaging System. We also determined the levels of ER stress markers in 3-bromopyruvate treated TC-1 cells. In vivo assay, TC-1 tumor-bearing mice were treated with 3-bromopyruvate (10mg/kg, intraperitoneal injection) and/or CRT/E7 DNA vaccine (30μg/mouse). The tumor mass size and survival were evaluated. Treatment of TC-1 cells with 3-bromopyruvate induced significant in vitro cytotoxicity. We found that treatment with 3-bromopyruvate led to upregulation of ER stress markers (CHOP, GRP78) in E7-expressing TC-1 tumor cells. More importantly, treatment with combination of 3-bromopyruvate and CRT/E7 DNA vaccine led to improved antigen-specific CD8+ T cell immune responses as well as therapeutic antitumor effects in TC-1 tumor-bearing mice. Thus, our data indicate that 3-bromopyruvate can enhance therapeutic HPV vaccine potency in generating improved antigen-specific immune responses and antitumor effects. These findings have important implications for future clinical translation.
Citation Format: Sung Yong Lee, JaeJeong Shim, Kang Kyung Ho, Kye Young Lee, Chien-Fu Hung, T.-C. Wu. Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B33.
Abstract B37: VSV-GP: A vaccine vector and oncolytic virus
Authors: Muik Alexander , Kimpel Janine , Tober Reinhard , Urbiola Carles , Laer Dorothee von 
Published: October 2015

Abstract
Oncolytic viruses have recently shown significant clinical benefits in several cancers. Interestingly, in addition to debulking the tumor by direct oncolysis, they were found to act as a cancer vaccine by setting free tumor antigen in the presence of virus-induced danger signals, which have an adjuvant effect. However, as oncolytic viruses induce neutralizing antibodies that inactivate the virus, oncolytic viruses are not delivered efficiently to cancer tissue upon repeated systemic application. Thus, repeated applications of oncolytic viruses have been restricted to intratumoral injections, which clinically has not been convincingly effective in metastatic disease.
We generated the oncolytic virus VSV-GP (Muik et al., Cancer Res, 2014) that is highly potent, lacks toxicity even at high doses (so far tested in mice and rabbits), can be produced at high titers and, above all, does not induce neutralizing antibodies readily. Thus, VSV-GP is unique among the oncolytic viruses in that it can be applied repeatedly without loosing efficacy. VSV-GP is highly effective leading to cure in several cancer mouse models, i.e. malignant glioma, melanoma, prostate cancer and ovarian cancer. In addition to oncolysis, VSV-GP induced a sound anti-tumor immune response and acted synergistically with other cancer immunotherapeutics. Moreover, VSV-GP was shown to be a highly promising vaccine vector and is the only replication competent viral vaccine vector that efficiently boosts the immune response upon repeated application. VSV-GP is thus a highly versatile replication competent viral vector platform for vaccination and cancer therapy.
Citation Format: Alexander Muik, Janine Kimpel, Reinhard Tober, Carles Urbiola, Dorothee von Laer. VSV-GP: A vaccine vector and oncolytic virus. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B37.
Abstract B63: The Macrophage Migration Inhibitory Factor promotes breast cancer metastasis through interaction with the host immune response
Authors: Balogh Kristen , Cross Janet 
Published: October 2015

Abstract
The Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that has been well-characterized as a mediator of numerous inflammatory disease processes. We have previously demonstrated that expression of MIF from the primary tumor is required for spontaneous pulmonary metastasis in the 4T1 murine model of breast cancer. MIF is overexpressed in many cancer types, including breast cancer, and the degree of MIF expression correlates with tumor aggressiveness. We therefore sought to understand the link between primary tumor expression of MIF and increased pulmonary metastasis. As a cytokine, we hypothesized that MIF would function by controlling some aspect of the interaction between the tumor and the host immune system. This was supported by our observation that MIF expression was no longer required for metastasis in an immunodeficient SCID/bg host. Using flow cytometry, we discovered that MIF expression in the primary tumor increased the abundance of a subset of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Furthermore, systemic depletion of MDSCs from tumor-bearing mice prevented spontaneous metastasis, suggesting that the MIF-induced increase in MDSCs is likely mediating the enhanced metastasis. Our subsequent observations suggest that MIF and MDSCs may be cooperating not only in the primary tumor, but also at sites of metastasis. Based on these results, we hypothesize that MIF and MDSCs are functioning to promote formation of a “pre-metastatic niche” in the lung. Ongoing studies aim to determine if MIF expression in the primary tumor is actively remodeling lung tissue to promote recruitment and/or differentiation of myeloid cells in the lungs. Metastatic disease is the most common cause of cancer mortality in patients with breast cancer, and gaining a better understanding of how MIF and MDSCs are working to induce metastasis could lead to significant therapeutic advancement for these patients.
Citation Format: Kristen Balogh, Janet Cross. The Macrophage Migration Inhibitory Factor promotes breast cancer metastasis through interaction with the host immune response. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B63.
Abstract B65: Dissecting the tumor myeloid compartment reveals rare activating antigen presenting cells, critical for T cell immunity
Authors: Broz Miranda , Binnewies Mikhail , Boldajipour Bijan , Nelson Amanda , Pollock Joshua , Erle David , Barczak Andrea , Rosenblum Michael , Daud Adil , Barber Diane , Amigorena Sebastian , Veer Laura J. van 't , Sperling Anne , Wolf Denise , Krummel Matthew F. 
Published: October 2015

Abstract
Incoming tumor-reactive cytotoxic T lymphocytes (CTL) are modulated by innate immune cells of the tumor microenvironment and we have used intravital live-imaging to characterize the predominant T cell-APC interactions there. To further hone in on the identities of the APC populations, we have extensively examined myeloid subset diversity across multiple spontaneous (GEMM) and ectopic models. Importantly, as a functional counterpart to the abundant tumor infiltrating macrophages, we have identified a small population of rare tumoral Dendritic Cells capable of robust antigen processing and T cell stimulation. We have identified the specific lineage requirements of these cells, dissecting the essential cytokines driving each tumor APC population. In addition we have found that T-cell dependent immune clearance relies upon these rare tumoral Dendritic Cells. Thus, through the dissection of the tumor myeloid compartment we have revealed a rare, yet highly stimulatory and targetable DC subset that could be exploited therapeutically to enhance anti-tumor immune responses locally.
This work is supported by the Genentech Foundation and the Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award.
Citation Format: Miranda Broz, Mikhail Binnewies, Bijan Boldajipour, Amanda Nelson, Joshua Pollock, David Erle, Andrea Barczak, Michael Rosenblum, Adil Daud, Diane Barber, Sebastian Amigorena, Laura J. van 't Veer, Anne Sperling, Denise Wolf, Matthew F. Krummel. Dissecting the tumor myeloid compartment reveals rare activating antigen presenting cells, critical for T cell immunity. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B65.