bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3982: Evaluating the effects of obesity on immune responses in renal tumors
Authors: Dempsey Francesca , Norian Lyse 
Published: March 2024

Abstract
Understanding the effects of obesity on cancer progression and treatment is a critically important area of research. Obesity is reaching epidemic proportions in our country and is known to increase the risk for many cancers, including renal cell carcinoma, which is among the ten most common cancers in both men and women. Our lab has shown that obesity leads to worse outcomes in advanced renal cancer patients treated with immunotherapy as compared to lean patients, but the cause for this difference is unknown. To investigate this further, we utilized a murine model with diet-induced obese mice and lean mice that were challenged with orthotopic renal tumors. The tumors grew out over three weeks and were harvested for flow cytometry staining. We stained for markers associated with immune function to better characterize what might be causing patients with obesity to be less responsive to immunotherapy. Our preliminary findings show that DIO mice had a greater tumor burden than lean controls over time. We also found that there compositional differences in multiple subsets of T cells in DIO versus lean mice. In the future, we will expand our murine studies to evaluate the phenotype and function of both tumor cells and immune cells. Additionally, we will continue these studies in human samples to further examine associations between obesity and immunotherapy outcomes.
Citation Format: Francesca Dempsey, Lyse Norian. Evaluating the effects of obesity on immune responses in renal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3982.
Abstract 4032: ATRA 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 , Jocobo Rashel , Tfayli Adam , Jing Zhe , Krysan Kostyantyn , Tran Linh , Dubinett Steven M. , Liu Bin 
Published: March 2024

Abstract
Lung cancer remains the deadliest form of cancer, claiming 1.8 million lives 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 harbors 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 an immunosuppressive 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 with increased tumor mutational burden (Kras G12D P53-/-Lkb1-/-; KPL-3M) 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. To understand ATRA-mediated anti-tumor effects, we performed single cell RNA sequencing (scRNA-seq) of KPL-3M murine tumors with or without 6 daily ATRA treatments. scRNA-seq analysis revealed 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 neutrophils in KPL-3M 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 Jocobo, Adam Tfayli, Zhe Jing, Kostyantyn Krysan, Linh Tran, Steven M. Dubinett, Bin Liu. ATRA 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 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4032.
Abstract 4044: Potentiated antitumor activity of poly-γ-glutamic acid combined with anti PD-L1 blockade on murine models of colorectal cancer
Authors: Jang Jae-Pyung , Yoo Chan-Hee , Hahm Kyung-Soo , Lee Do Young , Park Young-Chul , Choi Jae Chul 
Published: March 2024

Abstract
Objective: Immune checkpoint inhibitors(ICIs) have been shown to be key role in cancer therapy. Especially, antibodies targeting programmed cell death ligand1(PD-L1) promoted T cells to activate immune response against cancer cells. However, the current ICIs still have insignificant to motivate effective antitumor immunity by blocking PD-1/PD-L1 pathway and the regulatory network of PD-L1 by cytokines in the tumor microenvironment remains to be uncovered. Previously, we have reported the anti-cancer effects of combination treatment with a natural product, poly-γ-glutamic acid(γ-PGA), and PD-1 blockade. Now, we show that combination therapy with anti PD-L1 and γ-PGA can overcome the limits of ICIs and enhance anticancer effect in murine colorectal cancer.
Design: In vivo efficacy studies were performed by intraperitoneal injection of antibody targeting PD-L1 and oral administration of γ-PGA in C57BL/6 model transplanted with mouse tumor cell lines. Systemic changes in immunophenotype was measured by tumor volume size and body weight. The splenocyte was isolated from mice and the populations of myeloid-driven suppressor cells(MDSCs) and CD4/CD8 T cells were analyzed by FACS. Also, the significant cytokines activated by T- cell, IFN-γ and IL-2, were measured by ELISA.
Results and Conclusions: In murine model of colorectal cancer, γ-PGA and anti PD-L1 blockade combination therapy significantly improved anti-tumor activity compared with single agents. In addition, tumoral infiltration of CD8+ T cells and IFN-γ productions were increased by γ-PGA, and its antitumoral activity was attenuated by antibody-mediated depletion of these cells, indicating that g-PGA suppressed tumor growth in a CD8 T cell-dependent manner. Therefore, our results suggest that γ-PGA promote ICI-mediated antitumor responses by the transformation of "cold tumors" into “hot tumors”
Citation Format: Jae-Pyung Jang, Chan-Hee Yoo, Kyung-Soo Hahm, Do Young Lee, Young-Chul Park, Jae Chul Choi. Potentiated antitumor activity of poly-γ-glutamic acid combined with anti PD-L1 blockade on murine models of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4044.
Abstract 408: NEK1 phosphorylation modulates ERCC6 in transcription coupled nucleotide excision repair with implications for prostate cancer
Authors: Ogundepo Oluwatobi M. , De Benedetti Arrigo 
Published: March 2024

Abstract
NER operates through two distinct pathways: global genome repair (GGR) and transcription-coupled repair (TC-NER). TC-NER, as its name suggests, is specifically dedicated to rectifying lesions that obstruct the progression of RNA polymerase during active transcription. This process is imperative for the maintenance of cellular homeostasis, as lesions encountered by the transcription machinery can lead to stalling, erroneous transcription, and ultimately, deleterious cellular outcomes. At the heart of the TC-NER pathway lies ERCC6, a helicase orchestrating the repair of DNA lesions within transcribed regions of the genome. ERCC6 (AKA CS-B) plays a pivotal role in detecting and coordinating the repair of transcription-blocking lesions and has been implicated in a plethora of cellular processes underscoring its multifaceted nature and its broader impact on genome stability and cellular health, as exemplified by the severity of syndromes in individuals with loss-of-function mutations. In the US, compared to Caucasians (CC), AA are at higher risk for developing PCa and have more aggressive disease that is refractory to treatment, to some extent explained by genetic differences in some cases attributed to alterations of their “Repairome”. GWAS revealed that, unlike CC, 89% of AA-PCa have at least one mutation in NER pathway genes. A defect in ERCC6 activity, either through reduced expression or mutation (e.g., M1097V found frequently in AA) may result in impaired TC-NER. This may be compounded by aging or obesity-related oxidative stress, resulting in progressive accumulation of damaged bases (e.g., 8-OG) and consequent (cancer-propensity) mutations, the correction of which involves BER or NER. This was investigated in part with PCa cell lines engineered via CRISPR-SDM to carry that particular genomic mutation, by studying their sensitivity to UV and the efficiency of removal of CPDs in vivo. In addition, we have begun investigation of its function in the variants (engineered and naturally found in PCa. Lines) in vitro, after IP from cells, by studying its intrinsic ATPase activity. We have also identified the kinase NEK1 as an important novel interactor and regulator of ERCC6. We previously identified NEK1 as being an early regulator of the adaptive response of PCa cells to ADT.
Citation Format: Oluwatobi M. Ogundepo, Arrigo De Benedetti. NEK1 phosphorylation modulates ERCC6 in transcription coupled nucleotide excision repair with implications for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 408.
Abstract 4092: Characterizing the endogenous retroviral envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine
Authors: Maldonado Maria Del Mar , Iida Masafumi , Hernandez Maria Del Mar Gracia , Le Loc , Donahue Renee N. , Palena Claudia , Schlom Jeffrey , Hamilton Duane H. 
Published: March 2024

Abstract
Endogenous retroviruses (ERVs) are remnants of retroviral germline infections which occurred over the course of evolution and constitute between 5-8% of the human genome. Although ERV protein expression is typically silenced epigenetically in normal adult human tissues, previous studies have shown that some ERVSs, can be aberrantly expressed in multiple cancer types. This atypical expression of ERVs in tumors may represent a class of immunologically relevant tumor-associated antigens that can potentially be targeted clinically using therapeutic cancer vaccines. For the first time, this study evaluates the ERV envelope protein ERVMER34-1 as a potential target for a therapeutic cancer vaccine. We first assessed the expression of ERVMER34-1 in multiple tissues and found that ERVMER34-1 protein is absent in most healthy adult tissues and over expressed in multiple types of human carcinomas. ERVMER34-1 specific T-cells were detected in PBMCs of cancer patients but not healthy donors following an overnight stimulation. However, reactive T-cells are readily expanded from both healthy donor and cancer patient PBMCs following a 7-day in-vitro stimulation. Importantly, reactive CD8+ T cells selectively killed human carcinoma cells expressing the target antigen. Based on these findings, we rationally designed a ERVMER34-1 therapeutic cancer vaccine and assessed its immunogenicity and anti-tumor efficacy in established syngeneic murine tumors expressing the full-length ERVMER34-1 protein. Our rationally designed ERVMER34-1 cancer vaccine significantly mediated tumor regression and extended survival as a monotherapy and in combination with checkpoint blockade. Altogether, our work supports the clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1 as a potential first-in-class immunotherapeutic target for the therapy of several carcinoma types.
Citation Format: Maria Del Mar Maldonado, Masafumi Iida, Maria Del Mar Gracia Hernandez, Loc Le, Renee N. Donahue, Claudia Palena, Jeffrey Schlom, Duane H. Hamilton. Characterizing the endogenous retroviral envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4092.
Abstract 4177: High-throughput in vivo monitoring of splenomegaly and tumor burden in a murine breast cancer model
Authors: McMannus Craig , Czernuszewicz Tomek J. , Gessner Ryan C. , Peterson Jeffrey D. 
Published: March 2024

Abstract
Splenomegaly is a valuable parameter in mouse model cancer studies, as it can reflect the magnitude of cancer burden, hematopoietic activity, immune status, and can provide an indirect measure of cancer treatment efficacy. In liquid cancer models specifically (leukemia/lymphoma), spleen sizing is important as it is usually the only measure of in vivo tumor burden that can be assessed noninvasively without genetic labeling of tumor cells. Magnetic resonance imaging (MRI) and contrast-enhanced computed tomography (CT) are highly effective at evaluating spleen size in small animals. However, these techniques can impose limitations on large-cohort study designs due to high cost, long scan time, and ionizing radiation. Ultrasound is an alternative method with lower cost, high frame rate, and no ionization, but can suffer from poor inter-user variability, limited 2D field-of-view, and low throughput due to manual operation. In this work, we evaluated a novel 3D automated ultrasound scanner (Vega, Revvity, Inc.) for rapid assessment of splenomegaly in a murine cancer model. Female BALB/c mice (n=10) were implanted with 5e5 4T1 (ATCC) cells on the right flank. Mice were imaged at five timepoints over 25 days to track longitudinal progression of both spleen and tumor enlargement. Images were segmented manually in 3D using the “Slice Draw” and “Fill Between Slices” effects in SonoEQ v2.0.1 (Revvity, Inc.) to quantify tissue volume. After the final timepoint, mice were euthanized, and spleen weight was measured ex vivo. An additional cohort of age-matched mice without tumors (n=7) were imaged at the final timepoint to serve as controls. Imaging revealed a substantial enlargement of the spleen over time, from 30 ± 3 mm3 to 545 ± 105 mm3, representing an 18-fold increase. In the same time span, tumor volume grew to 1966 ± 87 mm3. Correlation analysis demonstrated good agreement between ultrasound volumes and ex vivo spleen weights (R² = 0.90). The results in this study demonstrate that noninvasive, nonlabelled quantification of murine spleen size with automated ultrasound is feasible, robust, and fast. The average time to acquire the spleen image for each mouse was less than 30 seconds. Future studies will apply this workflow in liquid cancer models, as well as explore using machine learning approaches to automatically segment spleen borders for faster data analysis.
Citation Format: Craig McMannus, Tomek J. Czernuszewicz, Ryan C. Gessner, Jeffrey D. Peterson. High-throughput in vivo monitoring of splenomegaly and tumor burden in a murine breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4177.
Abstract 4238: ModelingRET-rearranged non-small cell lung cancer (NSCLC): Generation of lung cell progenitors from patient-derived induced pluripotent stem cells (iPSCs)
Authors: Marcoux Paul , Hwang Jinwook , Desterke Christophe , Imeri Jusuf , Griscelli Annelise Bennaceur , Turhan Ali 
Published: March 2024

Abstract
Rearranged during Transfection (RET) oncogenic rearrangements can occur in 1-2% of lung adenocarcinomas. While RET-driven NSCLC models have been developed using various approaches, no model based on patient-derived induced pluripotent stem cells (iPSCs) has been described yet. Patient-derived iPSCs hold great promise for disease modeling. However, generating iPSCs with specific oncogenic drivers, like RET rearrangements, presents challenges due to reprogramming efficiency and genotypic variability within tumors. To address this issue, we aimed to generate lung progenitor cells (LPCs) from patient-derived iPSCs carrying the somatic mutation RETC634Y which is commonly associated with hereditary medullary thyroid carcinoma. Additionally, we have established a RETC634Y knock-in iPSC model to validate the effect of this oncogenic mutation during LPC differentiation. We successfully generated LPCs from RETC634Y iPSCs using a 16-days protocol and showed an overexpression of cancer-associated markers as compared to control iPSCs. Transcriptomic analysis revealed a distinct signature of NSCLC tumor repression, suggesting a lung multilineage lung dedifferentiation, along with an upregulated signature associated with RETC634Ymutation potentially linked to poor NSCLC prognosis. These findings were validated using the RETC634Y knock-in iPSC model, highlighting key cancerous targets such as PROM2 and C1QTNF6, known to be associated with poor prognostic outcomes. Furthermore, the LPCs derived from RETC634Y iPSCs exhibited a positive response to the RET inhibitor Pralsetinib, evidenced by the downregulation of the cancer markers. This study provides a novel off-the-shelf iPSC model of RET-driven NSCLC, paving the way for exploring the molecular mechanisms involved in RET-driven NSCLC to study disease progression and to uncover potential therapeutic targets.
Citation Format: Paul Marcoux, Jinwook Hwang, Christophe Desterke, Jusuf Imeri, Annelise Bennaceur Griscelli, Ali Turhan. ModelingRET-rearranged non-small cell lung cancer (NSCLC): Generation of lung cell progenitors from patient-derived induced pluripotent stem cells (iPSCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4238.
Abstract 4263: Prostate cancer cell-derived small extracellular vesicles regulate monocyte migration via STEAP4 and promote a monocyte transitional state
Authors: Naranjo Nicole M. , Testa Anna , Yadav Santosh K. , Naik Ulhas P. , Yu Lei , Kelly William K. , Liu Qin , Ding Jianyi , Yang Hushan , Tang Hsin Yao , Verrillo Cecilia E. , Hooper Craig D. , Languino Lucia R. 
Published: March 2024

Abstract
Our group has previously shown that prostate cancer (PrCa)-derived small extracellular vesicles (sEVs) are powerful cell communication mediators as they carry an array of proteins that have the ability to change recipient cell functions. Here, we describe a novel pathway of cancer cell-monocyte communication mediated by sEVs. Since sEVs carry cargoes that alter recipient cell phenotypes, we analyzed via proteomic analysis sEVs released from PC3 PrCa cells. Using CRISPR Cas9 methods, we downregulated IFIT3 (Interferon-induced proteins with tetratricopeptide repeats-3, member of the interferon-stimulated gene family) in PC3 PrCa cell (IFIT3KO). We then isolated sEVs from PC3 or IFIT3KO cells by using differential ultracentrifugation followed by iodixanol density gradient. Our proteomic analysis of IFIT3KO sEVs compared to PC3 sEVs shows that IFIT3 downregulation results in a significant upregulation of a metalloreductase, STEAP4 (six-transmembrane-epithelial antigen of the prostate 4), which is increased in PrCa cells and promotes PrCa cell proliferation and survival. STEAP4 is also known to promote an anti-inflammatory response in monocytes and macrophages. We then, investigated whether PrCa sEVs enriched in STEAP4 have a causal effect on monocyte functions and phenotype by using adhesion and migration assays as well as flow cytometry. Our results show that while all PrCa sEVs stimulate the adhesion of healthy donor or non-metastatic PrCa patient monocytes, only PrCa sEVs expressing STEAP4 increase their migration. In parallel, we provide evidence that all PrCa sEVs affect some of the M2 (CD163 or CD204) and M1 (CD80 or HLA DR) polarization markers analyzed in healthy donor monocytes. We show that there is a transitional state induced by PrCa sEVs in healthy donor monocytes, which occurs in a STEAP4-independent manner. This state mimics the non-metastatic PrCa patient monocyte phenotype. In conclusion, we describe a unique pathway whereby PrCa cell sEVs expressing STEAP4 promote monocyte migration with partial changes to their polarization.
Funding: This study was supported by NCI P01-CA140043, R01-CA224769, Pennsylvania DOH - Cure award to L.R.L
Citation Format: Nicole M. Naranjo, Anna Testa, Santosh K. Yadav, Ulhas P. Naik, Lei Yu, William K. Kelly, Qin Liu, Jianyi Ding, Hushan Yang, Hsin Yao Tang, Cecilia E. Verrillo, Craig D. Hooper, Lucia R. Languino. Prostate cancer cell-derived small extracellular vesicles regulate monocyte migration via STEAP4 and promote a monocyte transitional state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4263.