bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4963: Heme Sequestration as an effective strategy for the suppression of tumor growth and progression of SCLC
Authors: Ashrafi Adnin , Salamat Narges , Berisha Eranda , Alemi Parinaz Sadat , Castro Maria Del Carmen Chacon , Akter Zakia , Zhang Li 
Published: April 2023

Abstract
Small-cell lung cancer (SCLC) accounts for 15% of all lung cancers with exceptionally high proliferative rate, early metastasis, and poor prognosis. Chemotherapy has provided SCLC patients considerable survival benefits over the past three decades. Etoposide-platinum (EP) is the preferred first-line regimen. SCLC is initially highly responsive to cisplatin and etoposide chemotherapy, but in almost every case becomes rapidly chemo resistant. Despite attempts to improve outcomes utilizing multiple different strategies, drug resistance remains a major obstacle in clinical consequences of patients with SCLC. Recent research aims to elucidate mechanisms of resistance to improve drug response and treatment outcomes. Our lab has shown that limiting heme via inhibition of heme uptake using heme sequestering peptide (HeSP2) can delay growth and progression of NSCLC tumors. This HeSP2 can also effectively inhibit angiogenesis, normalize tumor vasculature, and alleviate tumor hypoxia in NSCLC tumors and thereby inhibit lung tumor advancement. Here we aim to determine if HeSP2 can be used to enhance the therapeutic efficacy of traditional chemotherapy in the treatment of SCLC. Our preliminary results show that HeSP2 can effectively reduce cell proliferation of SCLC cells like H889 and H720. To understand the mechanism by which the heme sequestering protein limit tumor development, we generated human SCLC H889 xenograft lung tumor model in NOD/SCID mice subcutaneously. Mice were treated with saline (control), HeSP2 alone, cisplatin-etoposide, and HeSP2-cisplatin-etoposide in combination. Tumor growth was monitored using caliper measurements. Tumors tissues were harvested, processed and paraffin embedded for immunohistochemistry (IHC) and histology experiments. The results imply that heme sequestration can be a potential strategy for suppressing small cell lung cancer tumor progression and improve survival outcome of patients.
Citation Format: Adnin Ashrafi, Narges Salamat, Eranda Berisha, Parinaz Sadat Alemi, Maria Del Carmen Chacon Castro, Zakia Akter, Li Zhang. Heme Sequestration as an effective strategy for the suppression of tumor growth and progression of SCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4963.
Abstract 5083: Investigating the development and therapeutic potential of intra-tumoral CXCR6+ effector/effector memory T cells (TEFF/EM) in triple-negative breast cancer
Authors: Lim Bryan Jian Wei , Wang Xiao-Fan , Li Qi-Jing 
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype that makes up 10-20% of all breast cancer cases. Because of the higher risk of metastasis and recurrence post-treatment, there is a need to develop novel therapeutics to address these challenges. In previously published work, we demonstrated that CXCL16 traps CXCR6+PD-1+ effector/effector memory (TEFF/EM) within the primary tumor and that these T cells have anti-metastatic function that can be harnessed when released into peripheral sites with intra-tumoral administration of anti-CXCL16 prior to surgical resection. However, whether CXCL16 blockade can be used in combination with conventional checkpoint targets and the developmental route of this CXCR6+ TEFF/EM is not known. To develop a novel neoadjuvant therapy, we use the spontaneously metastasizing murine TNBC model, 4T1. Here, we report that anti-4-1BB, and not anti-PD-1, when used in combination with blockade of CXCL16 can prolong survival post-surgical resection. Using anti-4-1BB in combination with CRISPR-generated Cxcl16-KO 4T1 model, we show that both deficiency of CXCL16 within the tumor microenvironment (TME) and anti-4-1BB contribute synergistically to survival advantage. To study the development of this population of T cells, we use the Py8119 murine TNBC model. We definitively show that CXCR6+PD-1+ TEFF/EM is uniquely generated within the primary tumor. Co-expression of CXCR6 and PD-1 indicates that T cell receptor (TCR) signaling is a potential regulator of the development of this TEFF/EM sub-population. Analyses of our previously published scRNA-seq dataset reveals Lat2 to be the top gene involved in TCR signaling. Tumors growing on Lat2-KO animals show a significant increase in tumor size accompanied by significant reduction of CD44high/mid CXCR6+PD-1+ TEFF/EM. However, competitive transfer of naïve WT and Lat2-KO T cells into Tcra-KO recipients led to comparable levels of CXCR6+ TEFF/EM. Surprisingly, transferred Lat2-KO T cells failed to engraft within the primary tumor relative to WT T cells. Future work will address if this engraftment defect is due to expansion/survival defects. Therefore, regulation of TCR signaling within the TME via LAT2 potentially represents a mechanism in which primary tumors trap T cells, promoting their exhaustion. Importantly, this can be harnessed through combinatorial activation and blockade of 4-1BB and CXCL16 respectively.
Citation Format: Bryan Jian Wei Lim, Xiao-Fan Wang, Qi-Jing Li. Investigating the development and therapeutic potential of intra-tumoral CXCR6+ effector/effector memory T cells (TEFF/EM) in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5083.
Abstract 5085: Blockade of tumor derived CSF1 promotes an immune-permissive tumor microenvironment
Authors: Maldonado Maria Del Mar , Hamilton Duane H. , Schlom Jeffrey 
Published: April 2023

Abstract
The macrophage colony stimulating factor 1 (CSF1) is a chemokine essential for the survival, proliferation, and differentiation of especially mononuclear phagocytes, such as macrophages and monocytes. However, within the tumor microenvironment (TME), CSF1 regulates the production, survival, and recruitment of tumor associated macrophages (TAMs), further promoting a protumorigenic and immunosuppressive M2-like phenotype. Overexpression of CSF1 in breast, prostate, and ovarian cancers has been shown to promote tumorgenicity, invasiveness, and accelerate tumor metastasis. In this study, we demonstrate for the first time, that treating established murine MC38 colon and 4T1 breast carcinoma tumors with a CSF1R blocking antibody promotes the expansion of neoepitope-specific T cells. To assess the role of tumor derived CSF1 in these model systems, we generated and characterized CSF1 CRISPR-Cas9 knockouts. In both models, elimination of tumor-derived CSF1 results in a decreased tumor growth in both syngeneic and immune-compromised mice as compared to the parental cell lines. Inhibition of CSF1/CSF1R signaling axis generated enhanced immunity against 4T1 and MC38 tumor neoepitopes, potentially promoting an immune permissive TME in tumor bearing mice. Combination of a neoepitope targeting cancer vaccine with anti-PDL1 in the MC38 CSF1-/- tumor model significantly decreased tumor growth in vivo. Furthermore, combining CSF1R blockade with adeno-TWIST1 vaccine decreased tumor volume, lung metastasis, and synergistically increased in CD8 T cell infiltration in 4T1 mammary tumors. Analysis of the tumor microenvironment demonstrated increased infiltration in CD8 T cells accompanied by a reduction in tumor associated macrophages following CSF1R inhibition in both tumor models. Our findings confirm the therapeutic potential of combining CSF1 targeting agents with vaccine agents to further modulate anti-tumor immune responses in the tumor microenvironment.
Citation Format: Maria Del Mar Maldonado, Duane H. Hamilton, Jeffrey Schlom. Blockade of tumor derived CSF1 promotes an immune-permissive tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5085.
Abstract 511: A small molecule CET019 inhibits progression of triple negative breast cancer
Authors: Dheeraj Arpit , Tailor Dhanir , Marques Fernando Jose , Grau Benedikt , Bermudez Abel , Pitteri Sharon , Malhotra Sanjay 
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, which accounts for 15-20% of total diagnosed breast cancer cases with high rates of metastasis and recurrence. Metastatic breast cancer remains one of the leading causes of cancer related mortality in women. The majority of women with this disease relapse after curative-intent therapy for early breast cancer; while a smaller proportion present with distant metastases at initial diagnosis. Our efforts of developing effective therapies for TNBC have identified CET019, a novel small molecule that effectively inhibits the growth of breast cancer cells. We found that CET019 impedes the clonogenic potential and growth of triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468, SUM159 and 4T1). CET019 treatment induces the G2/M phase cell cycle arrest in TNBC cells. Moreover, the mouse xenograft study with different TNBC models, found that CET019 inhibits growth and progression compared to vehicle control group. Metastatic nodules in the lungs were inhibited by CET019 compared to control group. Collectively, our in vitro and in vivo experiments, provide foundation to further develop CET019 as a potential drug candidate to treat patients with TNBCs.
Citation Format: Arpit Dheeraj, Dhanir Tailor, Fernando Jose Marques, Benedikt Grau, Abel Bermudez, Sharon Pitteri, Sanjay Malhotra. A small molecule CET019 inhibits progression of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 511.
Abstract 5146: In vitro neutrophil assays to support immuno-oncology drug development
Authors: Pieters Alanah , Vlaming Martijn , Lefevere Jezabel , Pattyn Sofie 
Published: April 2023

Abstract
Neutrophils have shown a lot of plasticity with important consequences on cancer disease progression and have been associated with multiple functions such as killing antibody-opsonized cancer cells, directly kill tumor cells through the release of reactive oxygen and nitrogen species and a controversial role in the tumor micro-environment with both pro- and anti-tumor roles. Studying neutrophil function in vitro can be done using the Incucyte® live imaging system to monitor antibody-dependent cell-mediated cytotoxicity (ADCC). Optimised in vitro assays using fresh human neutrophils and fluorescent-labeled tumor cells can be used to screen the potency of candidate therapeutics. Additionally, neutrophil chemotaxis can be monitored using transwell plates and live imaging via Incucyte®. Finally, multiplex cytokine and chemokine analysis after activation and stimulation of neutrophils can be evaluated using Luminex technology. When studying neutrophil activity in vitro, important factors such as access to fresh blood and optimized protocols for purifying untouched neutrophils are key for reproducible and reliable results.
Citation Format: Alanah Pieters, Martijn Vlaming, Jezabel Lefevere, Sofie Pattyn. In vitro neutrophil assays to support immuno-oncology drug development. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5146.
Abstract 5157: ATRA treatment induces an interferon response to reprogram the immunosuppressive tumor microenvironment and overcomes resistance to immune checkpoint inhibition in murine models of LKB1 deficient non small cell lung cancer
Authors: Crosson William P. , Li Rui , Salehi-Rad Ramin , Lim Raymond J. , Abascal Jensen , Kahangi Bitta P. , Reyes Edgar Perez , Oh Michael , Dumitras Camelia , Edgar Nico , Chew Ryan , Jacobo Rashel , Jing Zhe , Krysan Kostyantyn , Tran Linh M. , Dubinett Steven , Liu Bin 
Published: April 2023

Abstract
Lung cancer remains the deadliest form of cancer, claiming the lives of 1.8 million individuals worldwide in 2020. While treatment options have improved with the advent of immune checkpoint inhibitors (ICI), many patients do not respond to immunotherapy or develop resistance following initial response. A significant subset of non-small cell lung cancer (NSCLC) patients harbor somatic co-mutations in Kirsten rat sarcoma virus (KRAS) and Liver kinase 1 [LKB1, also known as serine/threonine kinase 11 (STK11)] genes, whose tumors are characterized by a predominance of neutrophils and an immune suppressive tumor microenvironment (TME) that are resistant to ICI. Our studies revealed that all-trans retinoic acid (ATRA), a metabolite derived from vitamin A, sensitized a murine model of NSCLC (Kras G12D P53−/−Lkb1−/−; KPL) to PD-1 blockade. The ATRA and anti-PD-1 combination therapy improved local and systemic T cell activation and generated systemic tumor-specific immunity. We further observed that ATRA augmented anti-PD-1 efficacy in additional murine NSCLC models with or without LKB1 loss. To understand ATRA-mediated anti-tumor effects, we performed single cell RNA sequencing (scRNA-seq) of KPL murine tumors with or without 6 daily ATRA treatments. scRNA-seq analysis indicated a reduction of neutrophils as well as an enrichment in T cell and natural killer (NK) cell populations in the TME. Furthermore, scRNA-seq analysis revealed elevated expression of interferon (IFN) downstream genes in multiple immune subpopulations in the TME. Preliminary ex vivo studies indicated that ATRA increases NOX2 levels, intracellular reactive oxygen species (ROS), and IFN signaling in the myeloid-derived suppressor cells (MDSC) of KPL tumors. Our findings suggest that ATRA may reshape the TME by activating IFN signaling in multiple cell subtypes to sensitize resistant tumors to ICI immunotherapy.
Citation Format: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Michael Oh, Camelia Dumitras, Nico Edgar, Ryan Chew, Rashel Jacobo, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Steven Dubinett, Bin Liu. ATRA treatment induces an interferon response to reprogram the immunosuppressive tumor microenvironment and overcomes resistance to immune checkpoint inhibition in murine models of LKB1 deficient non small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5157.
Abstract 5168: In vitro suppressive Treg bioassays for screening of candidate therapeutics
Authors: Vlaming Martijn , Pieters Alanah , Lefevere Jezabel , Pattyn Sofie 
Published: April 2023

Abstract
The increasing interest in the tumor microenvironment leads to a focus on new bioassays to represent all the players of the cancer immune response. Some of these players like regulatory T cells play an important role by downregulating the anti-tumor response. Their regulation mechanisms constitute an important target for new therapeutics. In order to study these mechanisms in a human model, suppressive Treg bioassays mimicking the suppressive action of these cells were developed and optimized. In vitro suppressive assays come with many technical challenges, therefore protocols for the purification and in vitro culture of regulatory T cells were optimized and fine-tuned to result in an optimal assay window e and allow screening of multiple candidates. Donor-to-donor variation is controlled by pre-evaluation of multiple donors and standardized methods are used for isolation and in vitro culture of responding and suppressive cells. Access to a large and broad panel of healthy donors is required for the evaluation of therapeutic agents targeting the regulatory T cell pathway.
Citation Format: Martijn Vlaming, Alanah Pieters, Jezabel Lefevere, Sofie Pattyn. In vitro suppressive Treg bioassays for screening of candidate therapeutics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5168.
Abstract 5178: Humanized OX40/OX40L mice as a tool for evaluating novel therapeutics
Authors: Liu Chonghui , Yao Jiawei , Zhou Xiaofei , Jin James , Zhang Zan 
Published: April 2023

Abstract
The use of immune-competent mouse models that express target human genes provide a promising preclinical platform aimed at developing novel immunotherapies. Emerging immunotherapies include targeting OX40 and OX40 ligand (OX40L), which can lead to enhanced T cell activation, proliferation, and effector function. Blocking the OX40/OX40L pathway improves autoantigen-specific T cell responses and decreases immunocompetence across several autoimmune diseases. To explore the potential of OX40 and OX40L antibody efficacy studies, we developed double humanized B-hOX40/hOX40L mice by replacing the extracellular domain sequences of murine Ox40 and Ox40l with the corresponding human sequences. We validated human OX40L gene expression by RT-PCR and OX40/OX40L protein expression by flow cytometry in B-hOX40/hOX40L mice. Additionally, percentages of splenic, blood, and lymph node immune cells were similar between B-hOX40/hOX40L and wild-type C57BL/6 mice. Altogether, this data demonstrates that B-hOX40/hOX40L mice are suitable for in vivo efficacy studies using anti-human OX40 and OX40L antibodies.
Citation Format: Chonghui Liu, Jiawei Yao, Xiaofei Zhou, James Jin, Zan Zhang. Humanized OX40/OX40L mice as a tool for evaluating novel therapeutics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5178.
Abstract 5376: Protein structure-based modeling to improve MHC class I epitope predictions
Authors: Wilson Eric A. , Cava John Kevin , Chowell Diego , Singharoy Abhishek , Anderson Karen S. 
Published: April 2023

Abstract
The ability to accurately identify peptide ligands for a given major histocompatibility complex class I (MHC-I) molecule has immense value for targeted anticancer therapeutics. However, the highly polymorphic nature of the MHC-I protein makes universal prediction of peptide ligands challenging due to lack of experimental data describing most MHC-I variants. To address this challenge, we have developed a deep convolutional neural network, HLA-Inception, capable of predicting MHC-I peptide binding motifs using electrostatic properties of the MHC-I binding pocket. By approaching this immunological issue using molecular biophysics, we measure the impact of sidechain arrangement and topology on peptide binding, feature not captured by sequence-based MHC-I prediction methods. Through a combination of molecular modeling and simulation, 5821 MHC-I alleles were modeled, providing extensive coverage across human populations. Predicted peptide binding motifs fell into distinct clusters, each defined with different degrees of submotif heterogeneity. Peptide binding scores generated by HLA-Inception are strongly correlated with quantitative MHC-I binding data, indicating predicted peptides can be ranked, both within and between alleles. HLA-inception also showed high precision when predicting naturally presented peptides and can be used for rapid proteome-scale MHC-I peptide binding predictions. Finally, we show that the binding pocket diversity measured by HLA inception predicts response to checkpoint blockade.
Citation Format: Eric A. Wilson, John Kevin Cava, Diego Chowell, Abhishek Singharoy, Karen S. Anderson. Protein structure-based modeling to improve MHC class I epitope predictions. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5376.
Abstract 5537: Prognostic impact of sarcopenia in patients with metastatic castration sensitive prostate cancer
Authors: Iwamoto Hiroaki , Izumi Kouji , Mizokami Atsushi 
Published: April 2023

Abstract
Background/Aim: Recently, sarcopenia has been reported to be a useful prognostic factor in cancer patients, including prostate cancer patients. Gleason score, the presence or absence of visceral metastases, and the number of bone metastases, which were used in the LATITUDE and CHAARTED trials, are known prognostic factors for metastatic castration-sensitive prostate cancer (mCSPC). Although a large proportion of patients with mCSPC are elderly, the significance of sarcopenia in metastatic castration-sensitive prostate cancer is unknown.
Patients and Methods: Of 193 patients with mCSPC treated at Kanazawa University Hospital between 2000 and 2019, 150 patients with confirmed CT at diagnosis were included. Sarcopenia was determined based on the definition of Martin et al. Overall survival and prognostic factors were retrospectively evaluated.
Results: The median age was 72 years, median PSA 241 ng/mL, Gleason score (GS) ≥ 9 in 91 patients, visceral metastases in 23 patients, and sarcopenia in 106 patients. 109 patients (72.7%) were diagnosed as high risk by Latitude risk classification and 105 patients (70%) were diagnosed as high volume by Charted risk classification. All cause death was 64 patients, and the median follow-up period was 38.2 months. The median overall survival was 69.6 months. On multivariate analysis, GS ≥9 (P &lt;0.0001, hazard risk =3.78), LDH ≥ 300 U/L (P &lt;0.0001, hazard risk =2.88), and sarcopenia (P=0.04, hazard risk=2.07) were significant independent poor prognostic factors predicting shorter OS. The prognosis could be significantly stratified into a high risk group if two or more of these three factors were met and a low risk group if one or less was met (44 months vs. 106.4 months, P=0.0001, hazard risk=2.91). This classification more clearly stratified prognosis than the LATITUD classification (55.1 months vs. 135 months, P =0.027, hazard risk =1.8) or the CHAARTED trial classification (52.9 months vs. 135 months, P =0.009, hazard risk =1.98).
Conclusion: Sarcopenia that can assess general status was considered useful in the prognostic evaluation of patients with mCSPC.
Citation Format: Hiroaki Iwamoto, Kouji Izumi, Atsushi Mizokami. Prognostic impact of sarcopenia in patients with metastatic castration sensitive prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5537.