bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B01: Enhancing radiotherapy by targeting inflammatory monocytes
Authors: Connolly Kelli , Linehan David , Gerber Scott 
Published: March 2017

Abstract
Approximately 50% of cancer patients receive radiotherapy (RT) at some point throughout their treatment. Nevertheless, RT alone does not often result in cures, making it necessary to develop new ways to enhance this treatment modality. It is now understood that the efficacy of RT relies in large part on the anti-tumor immune response that it elicits. However, we believe that RT acts as a double-edged sword as it results in the infiltration of anti-tumor effector cells as well as myeloid cells associated with immunosuppression. One type of these myeloid cells, known as inflammatory monocytes (IM), are precursors for many immunosuppressive cells and have been shown to promote the progression of cancer in various models. However, the role these cells play in modulating the immune response following RT is unknown. To explore this, we focused on the specific chemokine receptors CCR2 and CCR5 and the primary ligands for these receptors, CCL2 and CCL5 respectively, which are present on IM and have been shown to play a role in the recruitment of myeloid cells into tissues and tumors alike. Here, we locally treat syngeneic tumors in C57BL/6 mice with 15Gy RT in order to study the role of CCL2+CCR5+ IM after RT. We show that RT upregulates the expression of intratumoral CCL2 and CCL5 by tumor cells. We also demonstrate that RT subsequently induces the increase of CCR2+ CCR5+ monocytes in circulation as well as their increased infiltration intratumorally. Therefore, we hypothesized that inhibiting the CCL2/CCR2 and CCL5/CCR5 axes and therefore blocking the infiltration of this potentially immunosuppressive cell population could improve the efficacy of RT. Administering a dual CCR2/CCR5 inhibitor (CCR2/CCR5i) daily beginning two days before RT, we demonstrate that inhibition of IM, both intratumorally and in circulation, results in smaller tumor burden and sustained tumor free survival in radioresponsive tumors. Furthermore, the anti-tumor effects of RT and the enhanced response afforded by CCR2/CCR5i is dependent on CD8+ T cells. These data suggest that inhibiting specific chemokine axes augments the anti-tumor effects of the adaptive arm of the immune system. Future studies will address the mechanism and clinical significance of targeting immunosuppressive myeloid cells as a means to enhance the effector functions of anti-tumor T-cells and further augment the efficacy of RT.
Citation Format: Kelli Connolly, David Linehan, Scott Gerber. Enhancing radiotherapy by targeting inflammatory monocytes. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B01.
Abstract B08: Tumor-initiating cell associated macrophages play an essential role in tumorigenesis
Authors: Guo Xiaocan , Bin Zhao 
Published: March 2017

Abstract
Inflammation plays a critical role in different stages of tumor development such as initiation, progression, and metastasis. Macrophages are specifically recruited into human tumors and play a generally tumor-promoting role. However, whether macrophages are specifically recruited by tumor-initiating cells (TICs) and how they impact tumorigenesis in vivo have not been directly assessed. Here we show that single liver TICs induced by activation of the Hippo pathway effector YAP strongly recruits macrophages which we termed tumor-initiating cell associated macrophages (TICAMs). Eradication of TICAMs by repression of YAP-induced cytokine expression leads to clearance of TICs in a p53-dependent manner and completely eliminates tumorigenesis. Importantly, TICAMs are recruited to early human HCC lesions showing YAP activation. Our results demonstrate a new role of macrophages essential for tumorigenesis by associating with and promoting the survival of TICs from the single-cell stage. These findings suggest a unique opportunity for tumor prevention by blocking TICAMs.
Citation Format: Xiaocan Guo, Zhao Bin. Tumor-initiating cell associated macrophages play an essential role in tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B08.
Abstract B18: Noninvasive imaging of antitumor immune responses
Authors: Rashidian Mohammad , Dougan Michael , Ingram Jessica , Ploegh Hidde 
Published: March 2017

Abstract
By using the body's own immune response, immunotherapy may prove to be a turning point in the treatment of cancer. Predictors of a patient's response to immunotherapy remain to be defined, as actual responses are heterogeneous and difficult to study in real-time. Is it possible to predict the outcome of therapy for an individual patient? What is the behavior and what are the dynamics of immune cells in the tumor microenvironment? We need new methods to noninvasively explore the microenvironment of tumors and enumerate relevant cell types. Imaging the extent of infiltration of immune cells into tumors and identifying the relevant lymphocyte subsets is therefore essential. We developed single domain antibodies (VHHs, ~15 kDa) against a variety of lymphocyte surface antigens to image antitumor immune responses. VHHs were engineered to contain a sortase recognition tag, X-LPETGG, at their C-terminus to enable site-specific modification with tags of choice. We synthesized a substrate that contains both a click handle and a metal chelator, where the click handle can be used to attach a polymer, and the chelator is used to chelate a radiometal onto the VHH of interest. We thus produced VHHs equipped with a polyethyleneglycol (PEG) molecule to increase circulatory half-life and a chelator. C57/BL6 mice were injected with 89Zr-PEGylated VHHs, and images were acquired 24 h post injection. Images of the PEGylated-VHHs showed specific staining with low background in kidney and intestine. When we used 89Zr-labeled PEGylated-VHHs specific for CD8 or Class II MHC, secondary lymphoid structures, including the mesenteric lymph node, were clearly visible. Knock-out mice were used to establish specificity of PET imaging. Mice bearing panc02 tumors were imaged at 24 h p.i. and showed CD8 T cells infiltrating the tumor. We monitored the CD8-T cell response to immunotherapy in the B16 melanoma model by using the antiCD8 VHH. For animals that showed a response that led to regression of the tumor, the distribution of the signal was homogeneous throughout the tumor. It is thus possible to monitor antitumor immune responses. Noninvasive monitoring could therefore change how therapy is applied.
Citation Format: Mohammad Rashidian, Michael Dougan, Jessica Ingram, Hidde Ploegh. Noninvasive imaging of antitumor immune responses. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B18.
Abstract B21: Probing tumor heterogeneity and immune infiltration with Cyclic Immunofluorescence (CycIF), a robust, multiplexed imaging method
Authors: Lin Jia-Ren , Izar Benjamin , Hawthorne Sabrina , Nordberg Josh , Kaldjian Eric , Sorger Peter 
Published: March 2017

Abstract
Tumor microenvironment, defined by surrounding stromal/immune cells as well as blood vessels, plays an important role in disease progression and therapy resistance. Increasing understanding of the heterogeneity in both tumor and its microenvironment will be crucial to development more effective therapies. Recently, several studies employing state-of-the-art single-cell sequencing methods reveal enormous complexity in tumor microenvironment. However, the spatial information and cell-to-cell interaction could not be preserved in these dissociated cells. Immunofluorescence has been widely used in different fields of biological and medical research for decades. The ability to obtain in situ and single-cell information makes this technique particularly important in tumor biology. However, biochemical and optical constraints limit the number of signals that could be captured simultaneously within the same sample. We have developed the CycIF (Cyclic Immunofluorescence), an easy and low-cost method to increase the multiplexity of conventional immunofluorescence. The CycIF method has been first applied in pre-clinical drug discovery, cancer and stem cell biology with adherent cell cultures. In here, we modified the original CycIF method for IHC/IF on FFPE samples, and used that to probe tumor heterogeneity, microenvironment and immune infiltration in various types of tumors. Up to 30 different antigens/markers could be simultaneously detected in different tumor samples, and these makers represent a wide range of biological processes, including the key molecules for lymphocyte surface makers (CD45, CD4, CD8, CD20, CD11c), immune checkpoints (PD-1, PD-L1), stromal/EMT proteins (E-Cadherin, Vimentin), cell cycle regulators (CycD1, PCNA, Ki67, pRB, p21/CIP), signaling proteins (EGFR, pERK, pS6) and apoptosis mediators (p53, Bax, Bcl-2, Survivin). Our study not only provides the first detailed map of tumor and its immune microenvironment, but also illustrates a robust multiplexed imaging platform for probing tumor heterogeneity.
Citation Format: Jia-Ren Lin, Benjamin Izar, Sabrina Hawthorne, Josh Nordberg, Eric Kaldjian, Peter Sorger. Probing tumor heterogeneity and immune infiltration with Cyclic Immunofluorescence (CycIF), a robust, multiplexed imaging method. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B21.
Abstract B26: Immunomodulatory activity of Isatuximab
Authors: Srinivasan Srimathi S. , Wang Anlai , Song Zhili , Adrián Francisco 
Published: March 2017

Abstract
Isatuximab, previously known as SAR650984 is a naked chimeric IgG1 anti-CD38 monoclonal antibody. It is currently in clinical trials demonstrating single-agent activity in heavily pretreated relapsed/refractory multiple myeloma (RRMM). Isatuximab induces killing of CD38 positive tumor cells by triggering Fc dependent effector functions such as ADCC, ADCP and CDC, as well as Fc independent direct apoptotic effect. However, its effects in immune cells that express CD38 are emerging and are not yet well defined. The aim of this study was to investigate the effects of Isatuximab on immune effector cells, to better understand its anti-tumor mechanisms underlying the clinical benefit. Among immune sub-populations, Natural Killer (NK) cells and monocytes have the highest CD38 receptor density. Further, NK cells and monocytes play critical roles in immunity against cancer. We investigated Isatuximab's effect on these immune effector cells including their expansion, cytokine secretion and activation. Treatment (8 days at 1µg/ml) of 106 whole human peripheral blood mononuclear cells with Isatuximab induced expansion of NK and monocytes. In addition to enhance expansion, Isatuximab was able to induce the release of IFN-γ (~4000-7000 pg/ml) and TNF-α (~150-200 pg/ml) in NK cells in the absence of target cells. Incubation of Isatuximab (1µg/ml) for an hour also enhanced cytotoxic activity of human NK cells, both NK-92 cell line and isolated human NK cells, against CD38 negative K562 and JHH6 tumor cell lines. In the case of monocytes, Isatuximab activates phagocytosis by human monocytic cell line THP-1 and purified human monocytes. Furthermore, Isatuximab-activated NK cells can induce monocyte to M1 macrophage polarization through IFN-γ release in vitro. These findings collectively show evidence of Isatuximab being an immune-modulatory agent able to induce NK cell and monocyte activation. Further study is needed to determine whether Isatuximab's immunomodulatory activity could be utilized for the treatment of both CD38-positive and negative cancers by enhancing its anti-tumor function.
Citation Format: Srimathi S. Srinivasan, Anlai Wang, Zhili Song, Francisco Adrián. Immunomodulatory activity of Isatuximab. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B26.
Abstract B28: Improved therapeutic activity of agonistic, human anti-CD40 monoclonal Abs by selective FcγR-engagement
Authors: Dahan Rony , Barnhart Bryan C. , Korman Alan J. , Ravetch Jeffrey V. 
Published: March 2017

Abstract
The use of immunomodulatory mAbs to stimulate effective therapeutic anticancer immunity has shown clinical successes for the treatment of an increasing number of cancer types. An approach that is currently under clinical development uses agonistic anti-CD40 mAbs to induce APC activation, thereby harnessing the potency of the immune response to eradicate tumors. While engagement of the inhibitory Fcγ Receptor(FγγR)IIB is required for the in vivo agonistic activity of anti-mouse CD40 mAbs, a similar requirement for human mAbs has been disputed based on in vitro studies and in vivo studies performed either in wild-type or mouse FcγR knockout strains and thus fails to address the unique binding affinities and tissue distribution of human FcγRs. To overcome these limitations we generated and used unique mouse model fully humanized for its FcγRs and CD40, and revealed that FcγRIIB engagement is also essential for the activity of the human CD40 agonistic mAbs, while engagement of the activating FcγRIIA inhibits their activity. By engineering Fc variants of human mAbs with selective enhancement to FcγRIIB but not to FcγRIIA, significant improvement of antitumor immunity was observed in multiple tumor models. These findings highlight the necessity of optimizing the Fc domain for this class of therapeutic antibodies by using pre-clinical model that accurately reflects the unique affinities and cellular expression of human FcRs, thus providing a development approach for therapeutic human antibodies based on their requirement for selective FcγR interactions. Here we describe the selection of optimized next-generation Fc-engineered agonistic CD40 mAbs.
Citation Format: Rony Dahan, Bryan C. Barnhart, Alan J. Korman, Jeffrey V. Ravetch. Improved therapeutic activity of agonistic, human anti-CD40 monoclonal Abs by selective FcγR-engagement. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B28.
Abstract B71: Circulating PD-1+CD8+T cells reflect response to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer patients
Authors: Lee Sung Yong , Lee Sungjong , Oh Jee Youn , Min Kyung Hoon , Hur Gyu Young , Shim Jae Jeong , Kang Kyung Ho 
Published: March 2017

Abstract
The programmed death-1 (PD-1)/programmed cell death-1 ligand (PD-L1) pathway plays a crucial role in tumor evasion. Alteration in Epidermal Growth Factor Receptor (EGFR) and KRAS are oncogenic drivers in lung cancer and activation of this pathway is a critical event during lung tumorigenesis. However, how this oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. According to other report, expression of mutant EGFR in bronchial epithelial cells induces PD-L1 and PD-L1 expression is reduced by EGFR inhibitors in lung cancer cell lines with activated EGFR mutation. Thus, we evaluated the levels of PD-1+ T cells in peripheral blood according to the response of EGFR Tyrosine Kinase Inhibitors (TKIs) in Non-small Cell Lung Cancer (NSCLC) patients. Blood samples of NSCLC patients were obtained at baseline and after EGFR TKI treatment. Flow cytometry was used to detect PD-1 expressing CD4 or CD8 T cells. Total 53 patients were enrolled in the study. 17 patients had EGFR mutation and treated with EGFR TKIs. The expression of PD-1+CD8+ T cells in peripheral blood are increased according to their clinical stage. The expression levels of PD-1+CD8+ T cells significantly decreased after EGFR TKIs treatment (pretreatment vs. post-treatment 0.93±1.25% vs. 0.43±0.59%, P=0.006). Post/pre EGFR TKIs treatment ratio of PD-1+CD8+ T cells was lower in partial response group than stable disease group (0.19±0.17 vs. 0.9±0.68, P=0.017). So this result showed that PD-1+CD8+ T cells was more decreased in good responder group. EGFR mutant lung tumor inhibited antitumor immunity by activating PD-1 and PD-1 expression was reduced by EGFR TKI, which was proportional to treatment response. In conclusion, the change of PD-1+CD8+ T cell in peripheral blood may be a surrogate marker to predict EGFR TKIs treatment response.
Citation Format: Sung Yong Lee, Sungjong Lee, Jee Youn Oh, Kyung Hoon Min, Gyu Young Hur, Jae Jeong Shim, Kyung Ho Kang. Circulating PD-1+CD8+T cells reflect response to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B71.
Abstract B74: Development of Salmonella-based vaccine against mesothelioma
Authors: Xu Chen 
Published: March 2017

Abstract
Purpose: Salmonella-based vaccine can provide protection against different kinds of cancer, whether used alone or used as a vehicle to deliver heterologous proteins. In this study, the functionality of a live Salmonella-p24 vaccine as a prophylactic anti-tumor vaccine against murine mesothelioma was analyzed.
Experimental Design: Malignant murine mesothelioma cell was engineered to express GAG, an HIV capsid protein, regarding as an artificial tumor associated antigen. Attenuated Salmonella enterica serovar Typhimurium aroA strain was modifed to encode p24, derived from GAG. BalB/C mice were orally immunized with Salmonella-p24 vaccine thrice at 2-week interval. P24-specific humoral and cellular immune responses were examined by ELISA and ELISPOT, respectively. Protection against the challenge with GAG-expressing mesothelioma was also evaluated after immunization.
Results: P24 antigen was successfully expressed in the cytoplasm of an attenuated Salmonella enterica serovar thyphimurium aroA strain. Immunization of wild-type BalB/C by oral gavage could elicit specific anti-p24 humoral and cellular immune response. In vivo protection studies revealed that over 80% of the treated mice remained free of GAG-mesothelioma after challenge, whereas all mice in control group developed tumor growth.
Conclusions: This p24-Salmonella vaccine could efficiently prevent GAG-expressing mesothelioma tumor growth in mice.
Citation Format: Chen Xu. Development of Salmonella-based vaccine against mesothelioma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B74.
Abstract B89: The chimeric antibody NZ-12 or CAR T cells targeting human podoplanin possesses antitumor activity against orthotopic xenograft models
Authors: Kato Yukinari , Shiina Satoshi , Natsume Atsushi , Abe Shinji , Nishioka Yasuhiko , Ogasawara Satoshi , Kaneko Mika K. 
Published: March 2017

Abstract
Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, which is expressed in lymphatic endothelium. PDPN is also highly expressed in many cancers such as malignant pleural mesothelioma (MPM), lung cancer, and malignant brain tumors including glioblastoma (GBM). We previously developed a rat anti-PDPN monoclonal antibody NZ-1 (rat IgG2a, lambda), and a rat-human chimeric anti-PDPN antibody NZ-8 (human IgG1, kappa), which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against PDPN-positive cancer cells. Firstly, we demonstrated the antitumor effect of not only NZ-1/NZ-8 but also NZ-12 (human IgG1, lambda), a novel rat-human chimeric anti-PDPN antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a+) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human NK (CD56+) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Moreover, NZ-12 induced potent ADCC mediated by human MNC, compared with NZ-1/NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56+) cells in MPM orthotopic xenograft mice. Secondly, we constructed a lentiviral vector expressing chimeric antigen receptor (CAR) comprising NZ-1-based single chain variable fragment (scFv) with CD28, 4-1BB, and CD3zeta intracellular domains. CAR-transduced peripheral blood monocytes (PBMCs) were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. Taken together, PDPN-targeting antibody therapy or PDPN-targeting CAR T cell therapy might provide an efficacious therapeutic strategy for the treatment of MPM or GBM.
Citation Format: Yukinari Kato, Satoshi Shiina, Atsushi Natsume, Shinji Abe, Yasuhiko Nishioka, Satoshi Ogasawara, Mika K. Kaneko. The chimeric antibody NZ-12 or CAR T cells targeting human podoplanin possesses antitumor activity against orthotopic xenograft models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B89.
Abstract IA03: Anti-tumor T cells: You are what you eat
Authors: Cui Guoliang , Ho Ping-Chih , Amezquita Robert , Kaech Susan M. 
Published: March 2017

Abstract
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. In contrast, resting memory CD8 T cells depend less on high rates of glycolysis and more on fatty acid oxidation to persist, self-renew and respond to secondary infection. This talk will discuss the concept of metabolic checkpoints for immune cells in tumors, referring to the idea that the nutrients utilized by different types of T cells can affect both their energetic demands and their functionality. In particular, the metabolic state of exhausted T cells found in tumors is only recently starting to be studied. Our data in mouse models of cancer suggest that a glucose-poor, fatty acid-rich tumor microenvironment limits aerobic glycolysis, but promotes fatty acid uptake in tumor-infiltrating T cells, which suppresses tumoricidal effector functions and increases PD-1 expression. This talk will discuss recent analyses of the signaling pathways that respond to these nutrient alterations in T cells in tumors and how this may relate to new modalities of treatment in combination with checkpoint blockade.
Citation Format: Guoliang Cui, Ping-Chih Ho, Robert Amezquita, Susan M. Kaech. Anti-tumor T cells: You are what you eat. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA03.