bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1522: Tumor-associated fibrosis leads to an increase in T-cell exhaustion and impairs tumor control in non-small cell lung cancer
Authors: Panni Usman Y. , Shenoy Varun , Knolhoff Brett , Ahmed Faiz , Herzog Brett , Hawkins William G. , Olson John A. , DeNardo David G. 
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer-related mortality with non-small cell lung cancer (NSCLC) being the most predominant type. Recent studies have shown the efficacy of anti-PD1 inhibitors which improved overall survival. However, this efficacy is limited to a subset of patients due to the intrinsic tumor resistance to immune checkpoint inhibitors. Our group recently demonstrated that tumor-associated fibrosis negatively correlates with T cell-mediated immune response in lung cancer. This is largely dependent on Col13a1-expressing cancer-associated fibroblasts (CAFs), which result in recruiting the immunosuppressive macrophages and regulatory T cells while limiting dendritic cells and CD8 T cell infiltration. Here, we characterize the effect of fibrosis on the TME including TILs and macrophages using an orthotopic KRAS and P53-driven murine NSCLC model (KPL86-mCher model) with FITC-induced fibrosis.Fibrosis significantly increased the number of cancer-associated fibroblasts and collagen density in KPL86-mCher lung tumors. Following carboplatin + pemetrexed and Anti-PD1 treatment, we observed no increase in tumor-infiltrating CD4+ and CD8+ T cells or decrease in tumor burden when compared with the non-fibrotic tumors. Rather, we observed a significant increase in exhausted T cells marked by high Tim3, PD1, and TOX in fibrotic KPL86-mCher tumors. Corresponding to these impaired T-cell responses, we found an increase in tumor-infiltrating alveolar macrophages with immunosuppressive phenotype under fibrotic tumor conditions. Our data suggests that tumor-associated fibrosis leads to an increase in CD8+ T cell exhaustion as well as immunosuppressive macrophage infiltration in our spontaneously derived murine model on NSCLC. Overall, this indicates that targeting tumor fibrosis may significantly improve the efficacy of immunotherapy which would have translational implications for patients with immunotherapy-resistant NSCLC.
Citation Format: Usman Y. Panni, Varun Shenoy, Brett Knolhoff, Faiz Ahmed, Brett Herzog, William G. Hawkins, John A. Olson, David G. DeNardo. Tumor-associated fibrosis leads to an increase in T-cell exhaustion and impairs tumor control in 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 1522.
Abstract 1538: Impact of C-reactive protein on the efficacy of immune checkpoint inhibitors in non-small cell lung cancer
Authors: Li Wenyuan , Guo Hui 
Published: March 2024

Abstract
Background: Immune checkpoint inhibitors (ICIs) therapy has achieved remarkable success in the treatment of non-small cell lung cancer (NSCLC). Clinical studies have suggested a correlation between C-reactive protein (CRP) levels and treatment efficacy, but it remains unclear whether CRP can directly impact the efficacy. Therefore, we investigated the imapct of CRP on the efficacy of ICIs in NSCLC.
Methods: The tumor growth model was established in CRP knockout and wildtype mice by injecting LLC cells to evaluate the effect of CRP on tumor proliferation. The frequencies and phenotypes of macrophages and T cells in mouse tumors were detected by flow cytometry. The impact of CRP on macrophage polarization was evaluated using flow cytometry and IF, while its impact on T cell chemokines CCL5, CXCL9, and CXCL10 was analyzed by ELISA and qRT-PCR. mCRP and α-PD-1 were implemented in C57/BL6 mice injected with LLC cells to evaluate the effect of mCRP on tumor immunotherapy. The frequencies of T cells in mouse tumors were detected by flow cytometry. Expression of mCRP and infiltration of immune cells in human NSCLC tissues were analyzed using IHC.
Results: We found that tumor progression was enhanced and the proportion of tumor-infiltrated M1 macrophages was decreased in CRP knockout mice. Using human PBMC-derived macrophage and RAW264.7 cell lines, we demonstrated that the monomeric form of CRP, known as mCRP, induced M1 polarization of macrophages, leading to increased secretion of CCL5, CXCL9, and CXCL10. In tumor bearing mice, mCRP treatment enhanced anti-tumor immunity and suppressed tumor progression by increasing CD4+ and CD8+ T cell recruitment. Surprisingly, the combined treatment of mCRP and α-PD-1 induced more significant tumor regression than α-PD-1 treatment alone. Additionally, high level of mCRP in NSCLC tissues is correlated with a more inflamed tumor microenvironment phenotype.
Conclusion: mCRP can enhance the efficacy of immune checkpoint inhibitors in NSCLC by activating anti-tumor immunity.
Citation Format: Wenyuan Li, Hui Guo. Impact of C-reactive protein on the efficacy of immune checkpoint inhibitors in 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 1538.
Abstract 1576: The heterogeneity between pancreatic ductal adenocarcinoma with & without lymphovascular invasion
Authors: Zou Yiping , Xie Yongjie , Gao Song , Zhou Tianxing , Yu Jun , Hao Jihui 
Published: March 2024

Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant solid tumors, with a five-year survival rate less than 10%. Lymphovascular invasion (LVI) is a poor prognostic indicator for PDAC, yet the difference between tumors with or without LVI is unclear.
Methods We used scRNA-seq analysis on the PDAC tissue of 24 patients obtained from the National Genomics Data Center (Project number: PRJCA001063) to compare T-cell, macrophage, & cancer-associated fibroblast (CAF) heterogeneity between LVI-positive & LVI-negative PDAC. To validate the scRNA-seq results, complementary techniques, including multiple immunofluorescence assays & flow cytometry, were used. Additionally, we analyzed the characteristics of LVI-positive PDAC tumor cells.
Results LVI-positive PDAC thrives in an immunosuppressive microenvironment. We discovered that CD8+ T cells were more deficient in LVI-positive PDAC than in LVI-negative PDAC. Furthermore, the effective & cytotoxic markers (such as GZMB & IFN-γ) of CD8+ T cells also decreased in LVI-positive PDAC. M2 macrophage polarization was found to be higher in LVI-positive PDAC compared to LVI-negative PDAC. In addition, we discovered a more fibrotic TME signature in LVI-positive PDAC. LVI-positive tumor cells, in particular, had a mesenchymal transition phenotype & a hypoxic microenvironment.
Conclusions This study adds to our understanding of the intricate heterogeneity seen in LVI-positive PDAC. It sheds light on the distinct characteristics of LVI-positive PDAC & advances our understanding of its underlying biology.
Citation Format: Yiping Zou, Yongjie Xie, Song Gao, Tianxing Zhou, Jun Yu, Jihui Hao. The heterogeneity between pancreatic ductal adenocarcinoma with & without lymphovascular invasion [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 1576.
Abstract 1589: Integrated multiomics analysis revealed the significance of Transgelin in driving pancreatic cancer-associated fibroblast-mediated cancer progression
Authors: Shinjo Keiko , Wang Xingxing , Kumegawa Kohei , Maruyama Reo , Mii Shinji , Murofushi Yoshiteru , Suzuki Miho , Enomoto Atsushi , Kondo Yutaka 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is primarily characterized by a desmoplastic reaction, mainly consisting of cancer-associated fibroblasts (CAFs). In order to investigate the heterogeneity of CAFs, we initially conducted single-cell Assay for Transposase-Accessible Chromatin with high-throughput sequencing (scATAC-seq) using pancreas tissue from 12-week-old KPC (K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre) PDAC mouse models. We identified three clusters enriched with myofibroblast CAF (myCAF) gene markers and one cluster enriched with inflammatory CAF (iCAF) gene markers. Next, we performed single-cell RNA sequencing (scRNA-seq) on pancreas tissues from KPC mice. scRNA-seq revealed four distinct fibroblast clusters, each exhibiting characteristic gene expression profiles of normal fibroblasts, iCAF, myCAF and antigen-presenting CAF (apCAF). These findings suggest that CAFs in the myCAF cluster identified in scATAC-seq may have potential to differentiate into either myCAFs or other CAF subtypes based on certain cues. Next, we focus on the expression of myCAF marker genes, particularly two commonly used markers, Tagln and Acta2. Among myCAFs, two subtypes were identified: Tagln-positive and Acta2-positive CAFs, and Tagln-negative and Acta2-positive CAFs. To confirm our findings, we conducted Immunohistochemical analysis (IHC) on KPC pancreas samples. We observed CAFs that were positive for both Talng and αSMA exclusively in close proximity to tumor cells. Fibroblast expressing only αSMA mostly located in normal area. Tagln is known as an actin-binding protein and plays an important role in activated fibroblasts. Orthotopic PDAC mouse models using Tagln homozygous knockout mice showed a significant reduction in tumor weight compared to the wild-type mice (P = 0.0076). Indeed, we found that high TAGLN expression in PDAC samples was associated with poor survival, as demonstrated by the analysis of the TCGA dataset. These data suggest that myCAFs expressing TAGLN contribute to the promotion of PDAC growth. Targeting stromal TAGLN might be a potential therapeutic strategy to counteract PDAC progression.
Citation Format: Keiko Shinjo, Xingxing Wang, Kohei Kumegawa, Reo Maruyama, Shinji Mii, Yoshiteru Murofushi, Miho Suzuki, Atsushi Enomoto, Yutaka Kondo. Integrated multiomics analysis revealed the significance of Transgelin in driving pancreatic cancer-associated fibroblast-mediated cancer progression [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 1589.
Abstract 1637: EPHB4 is a key regulator of G1/S transition in hepatocellular carcinoma
Authors: Husain Abdullah , Chiu Elley Y. , Ma Hoi-Tang , Ho Daniel W. , Sze Karen M. , Chan Lo-Kong , Ng Irene O. 
Published: March 2024

Abstract
Effective therapeutic regimens against advanced hepatocellular carcinoma (HCCs) have recently improved but it remains very limited. Targeting receptor tyrosine kinases (RTKs) has proven to one of the main ways of achieving better survival outcome in HCC patients, yet the precise mechanism for this success remains to be elusive. We have systematically investigated the expression profiles of RTKs transcriptomic datasets i.e. The Cancer Genome Atlas - Liver hepatocellular carcinoma (TCGA-LIHC) (n=371) and our in-house cohort of paired i.e. HKU-QMH (n=41), and identified EPHB4 as one of the most abundantly expressed and frequently mutated RTKs in human HCCs. EPHB4 expression was found to be significantly correlated with Alpha Fetoprotein (AFP) expression, a factor commonly used in the diagnosis of HCCs. Furthermore, EphB4 has been demonstrated to play a regulatory role in VEGF/VEGFR-mediated angiogenesis, critical targets for current successful drugs. We confirmed abundant membrane EphB4 expression in HCC clinical specimens and human HCC cell line models using immunohistochemistry. Clinicopathological correlation analysis of EPHB4 mRNA expression revealed that its overexpression is associated with aggressive tumor features including presence of tumor microsatellite, liver invasion, venous invasion, and absence of tumor encapsulation. Functionally, stably knocking down EPHB4 (shEPHB4) resulted in a strong reduction of proliferation and self-renewal rates of multiple HCC cell lines in vitro. It significantly reduced tumor growth rates in subcutaneous and liver orthotopic models in vivo. Furthermore, limiting dilution assay showed EPHB4 plays a role in tumor initiation property of HCC cells. Mechanistically, we performed Gene Set Enrichment Analysis (GSEA) of transcriptome profiles for shEPHB4 with respective controls and found that knocking down EPHB4 causes HCC cells undergo drastic changes in several cell cycle checkpoints including G1/S transition. Using thymidine blockade, we further confirmed that knockdown of significantly hinders the transition of HCC cells from G1 to S phase of cell cycle. Our data suggests a strong link between EphB4 and cell cycle. Conclusion: We found EphB4 plays a functional role in regulating G1/S transition in human HCCs and understanding regulatory role of EphB4 on cell cycle progression may provide mechanistic insights into the how to effectively target HCC in the clinic.
Citation Format: Abdullah Husain, Elley Y. Chiu, Hoi-Tang Ma, Daniel W. Ho, Karen M. Sze, Lo-Kong Chan, Irene O. Ng. EPHB4 is a key regulator of G1/S transition in hepatocellular carcinoma [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 1637.
Abstract 1656: ISM6331, a novel and potent pan-TEAD inhibitor, exhibits strong anti-tumor activity in preclinical models of Hippo pathway-dysregulated cancers
Authors: Li Qi , Wan Jainfei , Liu Jinxin , Shang Jing , Yu Jiaojiao , Zhu Wei , Chen Celia X.-J. , Qiao Junwen , Wang Ling , Zhang Man , Ding Xiao , Bavadekar Supriya , Rao Sujata , Ren Feng , Zhavoronkov Alex 
Published: March 2024

Abstract
The Hippo-YAP/TAZ-TEAD signaling pathway plays critical roles in tumorigenesis and tumor progression. Genetic alterations of Hippo pathway regulators, such as NF2 or LATS1/2, have been shown to induce YAP/TAZ-TEAD transcriptional activity, promoting initiation and progression of many solid tumors. In addition, many studies have shown that YAP/TAZ-TEAD activation mediates resistance to multiple targeted therapies, particularly EGFR-KRas-MAPK pathway inhibitors. The TEAD family of transcription factors (TEAD1/2/3/4) share structural similarity and have overlapping functions in tumor development and TEAD auto-palmitoylation is critical for its interaction with YAP/TAZ and its transcriptional function. Therefore, blocking TEAD palmitoylation and allosterically disrupting YAP/TAZ-TEAD-mediated transcriptional regulation, is emerging as a promising approach for the treatment of tumors with Hippo pathway dysregulation.
In this work, ISM6331, a novel and potent TEAD inhibitor with excellent inhibition against TEAD1/2/3/4 was identified leveraging an AI generative model. ISM6331 reversibly binds to the TEAD palmitoylation site and significantly suppresses TEAD transcriptional activity. ISM6331 potently and selectively inhibited the growth of many Hippo pathway-dysregulated tumor cells and dose-dependently suppressed the expression of TEAD target genes in vitro. In NF2-deficient or LATS1/2-mutant in vivo mesothelioma models, ISM6331 exhibited promising anti-tumor efficacy as monotherapy in a dose-dependent manner from 3 to 30mg/kg. ISM6331 also showed synergism with EGFR or KRasG12C inhibitors in inhibiting tumor cell growth and overcame drug resistance in in vitro and in vivo models. In addition, ISM6331 showed excellent pharmacokinetic properties in multiple preclinical species and was well-tolerated in GLP-toxicity studies. In summary, ISM6331 has promising potential to treat Hippo pathway-dysregulated tumors as monotherapy as well as in combination with targeted therapies.
Citation Format: Qi Li, Jainfei Wan, Jinxin Liu, Jing Shang, Jiaojiao Yu, Wei Zhu, Celia X.-J. Chen, Junwen Qiao, Ling Wang, Man Zhang, Xiao Ding, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov. ISM6331, a novel and potent pan-TEAD inhibitor, exhibits strong anti-tumor activity in preclinical models of Hippo pathway-dysregulated cancers [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 1656.
Abstract 1688: Nuclear receptor coactivator SRC-1 promotes colorectal cancer immune escape by enhancing PD-L1 transcription and protein stability
Authors: Hong Yilin , Chen Qiang , Wang Zinan , Zhang Yong , Li Bei , Kong Xu , Mo Pingli , Xiao Nengming , Xu Jianming , Ye Yunbin , Yu Chundong 
Published: March 2024

Abstract
Programmed death-ligand 1 (PD-L1), one of the immunosuppressive molecules, overexpresses in multiple cancers and is critical for their immune escape. We previously showed that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability; however, the role of SRC-1 in CRC immune escape is unclear. Here, we demonstrated that SRC-1 was positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibited PD-L1 expression in both human and murine CRC cells and retarded murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration and antitumor activity of effector CD8+ T cells. Genetic ablation of SRC-1 in mice also decreased PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models. Taken together, our findings highlight a crucial role of SRC-1 in facilitating CRC immune escape and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment.
Citation Format: Yilin Hong, Qiang Chen, Zinan Wang, Yong Zhang, Bei Li, Xu Kong, Pingli Mo, Nengming Xiao, Jianming Xu, Yunbin Ye, Chundong Yu. Nuclear receptor coactivator SRC-1 promotes colorectal cancer immune escape by enhancing PD-L1 transcription and protein stability [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 1688.
Abstract 1700: Interplay of pioneer and chromatin remodeling factors: New insights into breast cancer mechanisms
Authors: Takaku Motoki , Cooper Mikhal , Saotome Mika 
Published: March 2024

Abstract
Eukaryotic cells utilize chromatin to package their genomic DNA, which can hinder transcription factor binding and gene activation. Pioneer factors, which can activate silent chromatin by binding to nucleosomes in closed (inactive) chromatin regions, thereby increasing chromatin accessibility, are essential in multiple developmental pathways. Their misregulation has been linked to various human diseases, including cancer. Yet, the involvement of pioneer factor mutations in tumorigenesis and tumor progression remains largely unexplored. GATA3 is one of the most frequently mutated genes in breast cancer. We and other groups found that a subset of GATA3 mutations promote tumor growth by redirecting luminal transcriptional network governed by Estrogen Receptor alpha (ER-alpha), FOXA1, and GATA3. Our genomics data also suggested that GATA3 requires multiple co-factors to maintain and establish active enhancers. Through IP-mass spectrometry, we identified several chromatin remodeling factors as potential GATA3 binding partners, with CHD4 being particularly notable. Our genomic data, including ChIP-seq, ATAC-seq, and RNA-seq, suggest that during GATA3-induced mesenchymal-to-epithelial transition (MET), CHD4 plays a critical role in maintaining closed chromatin structure, particularly at enhancer regions. Depletion of CHD4 results in the activation of chromatin and genes that are not essential for successful MET. Furthermore, we observed functional interactions between GATA3 and PARP1 in both luminal and basal breast cancer cells, with notable changes in GATA3 mutant cells. Through these studies, we aim to uncover epigenetic vulnerabilities in GATA3-altered breast cancer cells, ultimately contributing to the development of new breast cancer treatments.
Citation Format: Motoki Takaku, Mikhal Cooper, Mika Saotome. Interplay of pioneer and chromatin remodeling factors: New insights into breast cancer mechanisms [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 1700.
Abstract 1708: Transposable element derived enhancers in ovarian cancer
Authors: Nguyen Lily L. , Ivancevic Atma , Bitler Benjamin G. , Chuong Edward B. 
Published: March 2024

Abstract
There is global epigenetic dysregulation during transformation from normal to cancerous cells. One of the many consequences of this global epigenetic dysregulation is the reactivation of transposable elements (TEs). TEs compose roughly half of the human genome and are normally repressed through epigenetic mechanisms such as DNA methylation and histone modifications. Endogenous retroviruses (ERVs) are a class of TEs that contain long terminal repeats (LTRs) with putative gene regulatory motifs. LTRs can be co-opted to be pro-tumorigenic by becoming non-canonical promotors for oncogenic genes. While several examples of TE-derived promotors have been reported in cancer, the potential significance of TE-derived enhancers remains largely unexplored. Here, we utilized publicly available multi-omics datasets (bulk and single-cell ATAC-seq, bulk and single-cell RNA-seq, and chromatin profiling) in the context of ovarian cancer to determine if there are tumor specific, TE-derived-enhancers that have gene regulatory function. We used CRISPRi technology to functionally validate a putative TE-derived enhancer and gene regulatory axis. We discovered that on the bulk tissue level, several TE families are enriched at open chromatin sites and sites marked by H3K27Ac (enhancer mark) of ovarian tumors, suggesting the presence of tumor specific, TE-derived enhancers. On the single-cell level, we discovered that ovarian cells have the highest expression of these TE transcripts compared to stromal and immune cells in the tumor microenvironment, suggesting that the increased TE-derived enhancer activity observed on the bulk level are specific to ovarian cells. Lastly, when we silenced a specific LTR18 locus upstream of a gene, TIPARP, TIPARP gene expression was also repressed, suggesting that these putative TE-derived enhancers have gene regulatory function. Determining the regulatory role of these TE-derived enhancers will provide novel insights into cancer-related transcriptomes.
Citation Format: Lily L. Nguyen, Atma Ivancevic, Benjamin G. Bitler, Edward B. Chuong. Transposable element derived enhancers in ovarian 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 1708.