bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A141: Intratumoral depletion of regulatory T-cells using CD25-targeted photodynamic therapy induces antitumoral immune responses
Authors: Lee Heung Kyu , Oh Dong Sun 
Published: February 2019

Abstract
Tumor immunotherapy aims to overcome the immunosuppressive microenvironment within tumors, and various approaches have been developed. Tumor-associated T regulatory cells (Tregs) suppress the activation and expansion of tumor antigen-specific effector T-cells, thus providing a permissive environment for tumor growth. Therefore, optimal strategies need to be established to deplete tumor-infiltrated Tregs because systemic depletion of Tregs can result in reduced anti-tumor effector cells and autoimmunity. Here, to deplete Tregs selectively in tumors, we intratumorally injected anti-CD25 antibodies conjugated to Chlorin e6 (Ce6), a photosensitizer that absorbs light to generate reactive oxygen species. Local depletion of tumor-associated Tregs by photodynamic therapy (PDT) inhibited tumor growth, which was likely due to the altered tumor immune microenvironment that was characterized by increased infiltration of CD8+ effector T-cells and the expression of IFN-γ and CD107a, which is cytolytic granule exocytosis marker, in tumor tissues. Furthermore, PDT-induced intratumoral Treg depletion did not influence adaptive immune responses in a murine influenza infection model. Thus, our results show that intratumoral Treg-targeted PDT could specifically modulate tumor microenvironments by depleting Tregs and could be used as a novel cancer immunotherapy technique.
Citation Format: Heung Kyu Lee, Dong Sun Oh. Intratumoral depletion of regulatory T-cells using CD25-targeted photodynamic therapy induces antitumoral immune responses [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 A141.
Abstract A143: Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and target for immunotherapy
Authors: Logtenberg Meike Emma Willemijn 
Published: February 2019

Abstract
Cancer cells are able to evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. CD47 serves as a “don't eat me” signal for myeloid cells by binding to the inhibitory receptor signal-regulatory protein alpha (SIRPα). Prior work has provided strong evidence that antibody-based targeting of the CD47 axis can promote tumor control by both innate and adaptive immune cells, and clinical development of CD47 antagonists is ongoing. Using a haploid genetic screen, we identify glutaminyl-peptide cyclotransferase-like (QPCTL) as a regulator of the CD47-SIRPα checkpoint that is critical for pyroglutamate formation on CD47 at the SIRPα binding site. Both genetic and pharmacologic interference with QPCTL activity decrease SIRPα binding to CD47 and enhances antibody-dependenT-cellular phagocytosis and cellular cytotoxicity of tumor cells mediated by macrophages and neutrophils, respectively. Furthermore, interference with QPCTL expression leads to a major increase in tumor cell killing and neutrophil influx by tumor-opsonizing antibodies in vivo. These data provide an avenue for small-molecule inhibition of the CD47 pathway to augment antibody therapy of cancer.
Citation Format: Meike Emma Willemijn Logtenberg. Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and target for immunotherapy [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 A143.
Abstract A145: Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC
Authors: Mugarza Edurne , Maldegem Febe van , Sopena Miriam Llorian , Arcas Miriam Molina , Downward Julian 
Published: February 2019

Abstract
Cancer immunotherapies such as immune checkpoint blockade have yielded long-term durable responses in some patients. Nevertheless, the majority of cancer patients do not respond to such therapies, which constitutes a large unmet need in the clinic. Tumors develop mechanisms by which they are able to evade the actions of the immune system, some of which may render them unresponsive to drugs aimed to boost antitumor immunity. Lung cancer is a highly immunogenic tumor type in which, if effective, cancer immunotherapies have proven to be superior to other treatment modalities. KRAS is an oncogene mutated in a third of lung cancer patients and has been previously shown to trigger immunosuppressive actions by tumour cells. We aim to study the immunosuppressive effects of KRAS mutations in vitro and in clinically relevant mouse models of lung adenocarcinoma. We have generated a tumor cell autonomous KRAS- dependent gene expression profile using in vitro systems. We have set a particular focus on genes playing a role in tumor immune evasion, whose function we are aiming to elucidate using immunogenic in vivo models. We have developed a derivative of the transplantable KRAS mutant murine Lewis lung adenocarcinoma (LLC) cell line in which KRAS activity can be specifically blocked using a small-molecule inhibitor. We aim to unravel the immune infiltration of such tumors and elucidate the specific role of KRAS in shaping its microenvironment. By combining simplistic in vitro models to unravel mechanisms of action and more complex mouse models to prove their clinical relevance, we aim to increase immune visibility of KRAS-mutated lung tumors to make them more susceptible to immune and other therapies.
Citation Format: Edurne Mugarza, Febe van Maldegem, Miriam Llorian Sopena, Miriam Molina Arcas, Julian Downward. Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC [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 A145.
Abstract A155: Antibody-dependent cancer cell phagocytosis in macrophages induces immune escape by upregulating PD-L1 and IDO
Authors: Su Shicheng , Su An 
Published: February 2019

Abstract
Therapeutic antibodies can exert anticancer effects via antibody-dependenT-cellular cytotoxicity (ADCC). Also, they may trigger antibody-dependenT-cellular phagocytosis (ADCP) in tumor-associated macrophages (TAMs), but how ADCP influences TAM functions and antitumor immunity remains unclear. Here, we demonstrated that TAMs undergone ADCP of breast cancer cells and lymphoma cells mediated by trastuzumab and rituximab, respectively, suppressed the proliferation and cytotoxicity of NK cells and tumor-specific CD8+ T-cells against tumor cells by increasing PD-L1 and IDO. In vivo, inhibition of PD-L1 and IDO dramatically increases the infiltration of NK cells and CD8+ T-cells in Her2+ breast cancers and enhances the therapeutic effects of anti-Her2 antibody in both human Her2 knockin mice and humanized mice. Clinically, trastuzumab, but not chemotherapy alone, significantly increased the expression of PD-L1 and IDO in the TAMs of Her2+ breast cancer patients receiving neoadjuvant therapy. Furthermore, PD-L1+ IDO+ TAM infiltration was associated with poor trastuzumab response and reduced NK and CD8+ T-cells in tumors. Collectively, our findings unveil an unexpected role of ADCP mediated by therapeutic monoclonal antibodies in cancer immunosuppression, and suggest that antibody plus immune checkpoint blockade provide synergic therapeutic effects in cancer patients.
Citation Format: Shicheng Su, An Su. Antibody-dependent cancer cell phagocytosis in macrophages induces immune escape by upregulating PD-L1 and IDO [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 A155.
Abstract A200: Targeting ICOS receptor for development of cancer immunotherapy
Authors: Lo Yu-Hsun , Yu Cheng-Chou , Yu Shu-Han , Hseih Tsung-Hang , Chan Mei-Chi , Shih-Chong Tsai 
Published: February 2019

Abstract
Recently, checkpoint blockade-mediated immune reinvigoration acts as potential strategies to cure cancer. In addition to checkpoint blockade, a number of studies have shown that immune co-stimulators also act as crucial players in the immunotherapy. Inducible co-stimulator (ICOS), a homodimeric protein that belongs to CD28 superfamily, is expressed on activated T-cells and resting memory T-cells. Upon stimulation, ICOS and its ligand ICOSL (B7RP-1, B7H-2) have been shown to affect T-cell responses via ICOS-mediated PI3-kinase signaling to enhance the T-cells’ development and activity. In addition, previous studies have shown that ICOS/ICOSL pathway may play an important role in CTLA4 inhibitor-induced tumor immunity. In this study, we aim to develop and implement the Fc-fusion recombinant ICOSL proteins to induce T-cells’ activation for therapeutic use. Our data suggested that recombinant ICOSL-Fc can enhance the proliferation and cytotoxicity effect of human T-cells by increasing INF-γ and IL10 secretion. Moreover, ICOSL-Fc can also inhibit tumor growth in xenograft animal models. Based on our study, ICOS/ICOSL pathway could be a promising therapeutic target for the immunotherapy.
Citation Format: Yu-Hsun Lo, Cheng-Chou Yu, Shu-Han Yu, Tsung-Hang Hseih, Mei-Chi Chan, Tsai Shih-Chong. Targeting ICOS receptor for development of cancer immunotherapy [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 A200.
Abstract A202: Lysophosphatidic acid impedes the effector function of CD8+ T-cells through LPA5R
Authors: Mathew Divij , Strauch Pamela , Pelanda Roberta , Torres Raul 
Published: February 2019

Abstract
Immunotherapies have demonstrated the utility of targeting the immune system for the eradication of tumors, yet a majority of patients remain refractory to such treatments. Therefore, further advances in our understanding of T-cell activation and inhibitory signals are required to find alternative combinational strategies to treat cancers. Lysophosphatidic acid (LPA) is a bioactive lipid that has been characterized to promote tumor growth via distinct mechanisms and thus displays multiple “hallmarks” of tumorgenesis, including enhancing tumor-promoting inflammation, metastasis, and angiogenesis. Despite LPA receptors (LPARs) being expressed on all immune cells, the impact of LPA on immune cells remains unclear. Work from our lab has previously shown that LPA signals via LPAR5 expressed by CD8+ T-cells to suppress TCR-mediated intracellular calcium mobilization. Thus, we propose that aberrant expression of LPA by diverse tumors serves also to dampen adaptive immune responses, thereby creating an immune suppressive tumor microenvironment. Here, we demonstrate that CD8+ T-cells express three of the six known LPA receptors, and that LPA signaling through LPA5R on CD8+ T-cells has not only a profound inhibition of Ca2+ release after TCR stimulation, but also impedes ERK and Nur77 TCR induced signaling pathway. Importantly we now demonstrate that LPA signaling also decreases the cytolytic function of CD8+ T-cells by inhibiting granule exocytosis. Both adoptive transfer of Lpar5-/- CD8+ T-cells and implantation of tumors into Lpar5-/- hosts leads to greater control of tumor growth, underscoring an immunosuppressive signal mediated by LPA through LPA5R on CD8+ T-cells. Finally, human CD8+ T-cells also express the same LPARs as in the mouse and similarly fail to efficiently release Ca2+ upon TCR stimulation in the presence of LPA. Pharmaceutical inhibition of the human LPA5 receptor restores Ca2+ flux, suggesting a similar mechanism seen in mice. Thus, our data illuminate a novel lipid-receptor interaction that suppresses CD8+ T-cell function in both human and murine cells.
Citation Format: Divij Mathew, Pamela Strauch, Roberta Pelanda, Raul Torres. Lysophosphatidic acid impedes the effector function of CD8+ T-cells through LPA5R [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 A202.
Abstract A203: Role of nonimmune functions of regulatory T-cells in inflammation and tissue homeostasis
Authors: Mendoza Alejandra 
Published: February 2019

Abstract
Regulatory T-cells (Treg) are a T-cell lineage vital to promoting tolerance to self antigens, commensal bacteria, and environmental antigens, as well as limiting responses to acute and chronic infections. Because of their critical role in immunosuppression in diverse biologic settings—including the tumor microenvironment—therapeutic targeting of Treg cells holds promise for cancer immunotherapy. In addition to dampening immune responses against tumor antigens and the associated inflammation, tissue-resident Treg cells may directly support tumor growth, homeostasis, and metastasis. Hence, understanding Treg cell functions independent from immunomodulation may provide novel targets for cancer therapy without the adverse side effects associated with immune checkpoint blockade. Studies of Treg cells found in non-lymphoid tissues have revealed transcriptional signatures and functions distinguishable from those found in Treg cells residing in secondary lymphoid organs, suggesting that Treg cells may perform a variety of specialized functions within non-lymphoid tissues. In addition, Treg cells can show distinct localization within non-lymphoid organs, raising the possibility that they may interact with different immune and non-immune tissue resident cells. In particular, we find frequent Treg cell localization in close proximity to peripheral neurons. Gene expression analysis has revealed expression of neuromodulatory molecules by Treg cells, further suggesting interplay between Treg cells and peripheral neurons. Interactions between Treg cells and the peripheral nervous system may play an important role in limiting immune responses and/or promoting tissue homeostasis. Understanding potential neuromodulatory activity of Treg cells and its effect on inflammation, tissue homeostasis and cancer could reveal novel strategies for therapeutic possibilities.
Citation Format: Alejandra Mendoza. Role of nonimmune functions of regulatory T-cells in inflammation and tissue homeostasis [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 A203.
Abstract A222: Exploiting mTORC1-independent protein synthesis in Tregs to boost antitumor immune response
Authors: Volta Viviana , Ernlund Amanda , Parra Columba De la , Gadi Abilash , Valeta-Magara Amanda , Schneider Robert J. 
Published: February 2019

Abstract
Regulatory T-cells (Tregs) maintain immune system homeostasis in the organism. In the tumor micro-environment, however, Tregs can hinder antitumor immune response. Treg maturation in peripheral sites (pTregs) requires inhibition of protein kinase mTORC1, which paradoxically blocks mRNA translation. mTORC1 phosphorylates (inactivates) 4E-BP1, a negative regulator of the translation initiation factor eIF4E. When mTORC1 is active, 4E-BP1 is hyperphosphorylated and releases eIF4E, which can then bind the mRNA cap structure and promote eIF4F complex assembly and ribosome recruitment. Inhibition of mTORC1 results in hypo-phosphorylation (activation) of 4E-BP1, which then binds and sequesters eIF4E, preventing its interaction with the cap and ribosome association to the mRNA. Using human CD4+ T-cells differentiated in vitro, we show that mTORC1 inhibition strongly impairs protein synthesis, yet with exposure to TGFbeta, is essential to mediate iTreg differentiation and immune suppression activity. We found that TGFbeta reprograms the T-cell transcriptome, while mTORC1 inhibition reprograms the translatome (genome-wide translation signature), mediating Treg differentiation. Genome-wide transcription and translation profiling identified TGFbeta-upregulated mRNAs resistant to mTORC1 inhibition, in part due to their 5’-untranslated regions, that induces Treg differentiation and immune suppression activity. These include canonical pTreg fate-determining mRNAs FOXP3, CTLA-4, CD101 and CD103, among others. Inhibition of mTORC1 alone or TGFbeta alone induces iTregs with poor immune suppression activity. Treg differentiation is therefore mediated by an mTORC1-independent privileged mRNA translation mechanism that converts activated CD4+ T-cells to Tregs. These findings are quite relevant in the tumor microenvironment, where mTORC1-inhibiting conditions such as hypoxia and deprivation of nutrients and energy are present. Investigation of molecular targets acting in this mTORC1/eIF4E-independent translation of Treg mRNAs is ongoing. These targets could be drugged to selectively inhibit Treg differentiation in the tumor microenvironment, thus allowing effector cells to mount the response against cancer cells.
Citation Format: Viviana Volta, Amanda Ernlund, Columba De la Parra, Abilash Gadi, Amanda Valeta-Magara, Robert J. Schneider. Exploiting mTORC1-independent protein synthesis in Tregs to boost antitumor immune response [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 A222.
Abstract B009: New development of monoclonal antibodies targeting TRAIL agonist receptors
Authors: Dubuisson Agathe 
Published: February 2019

Abstract
Restoring programmed-cell death of cancer cells is a real challenge in oncology. To date, several monoclonal antibodies targeting TRAIL agonist death receptors have been developed, but none has been found to display significant clinical effects, so far. Efforts should be continued to develop novel DR4 and DR5 antibodies with improved properties. In this regard, novel monoclonal antibodies targeting DR4 and DR5 have been generated here using DNA-immunization in order to produce antibodies that can recognise DR4 or DR5 in their native forms. This cost- and time-effective technique allows the production of proteins of interest directly into the mice. Plasmids encoding DR4 or DR5 sequences have been injected into the tail veins of mice. Immunizations elicited significant humoral anti-DR4 and anti-DR5 responses and fusions of the corresponding spleens resulted in numerous hybridomas that can specifically recognise DR4 or DR5 in their native forms. After an intensive screening, anti-DR4 and anti-DR5 clones were selected for production and 4 to 5 were assessed for selectivity and affinity towards their respective targets by flow cytometry (FACS) and bio-layer interferometry (BLI). All antibodies efficiently bind to their targets with a very high affinity (nanomolar range). They were then characterized and tested for their capacity to induce apoptosis in a wide range of cancer cell lines. Of the four anti-DR4 antibodies of interest, one antibody displayed agonistic properties alone, one was able to inhibit and two were found to potentiate TRAIL-induced apoptosis. Similarly, one out of the four anti-DR5 antibodies behaved as an agonist whereas another one was found to enhance TRAIL. The most potent antibody was assessed in vivo, and preliminary results indicate that the latter is also able to inhibit tumor growth in animal models. In summary, this study is the first demonstration that DNA-based immunization method can be used to generate efficient therapeutic monoclonal antibodies targeting receptors of the TNF superfamily.
Citation Format: Agathe Dubuisson. New development of monoclonal antibodies targeting TRAIL agonist receptors [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 B009.
Abstract B013: Site specific conjugation of engineered non-native amino acids in an anti-CD3 Fab-folate bispecific antibody significantly enhances its antitumor properties in gynecologic cancers
Authors: Gray Michael J. , Barkho Wisam , Tipton Barbara , Shastri Prathap , Jie Hyun-Bae , Steen Jeff , Frank Rik , Tian Feng , Jackson Dowdy , Zhang Shawn 
Published: February 2019

Abstract
Ovarian cancer is the seventh most commonly diagnosed cancer in women. Standard treatments typically include surgery followed by radiation and/or chemotherapy. However, currently 5-year survival rates are 44%, underlining the need for new effective therapies. The Folate receptor 1 (FOLR1, FRα) is expressed in 80% of ovarian tumors, making it an attractive target for CD3-based bispecific antibody therapies. Bispecific engagement of activated host T-cells in the tumor microenvironment is highly effective at eliminating tumor cells. We have developed an anti-CD3 Fab-folate bispecific antibody by engineering non-native amino acids (NNAAs) at a specific region within the Fab domain and conjugated a PEGylated folate molecule to these sites. Our data demonstrate that Ambrx’s proprietary site-specific conjugation technology provides significant advantages over non-PEGylated proteins.
Citation Format: Michael J. Gray, Wisam Barkho, Barbara Tipton, Prathap Shastri, Hyun-Bae Jie, Jeff Steen, Rik Frank, Feng Tian, Dowdy Jackson, Shawn Zhang. Site specific conjugation of engineered non-native amino acids in an anti-CD3 Fab-folate bispecific antibody significantly enhances its antitumor properties in gynecologic cancers [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 B013.