bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3721: EZH2 inhibition enhances PD-L1 protein stability through USP22-mediated deubiquitination in colorectal cancer
Authors: Yang Jianling , Huang Jiaqi , Yin Qianqian , Xue Lixiang 
Published: March 2024

Abstract
The regulation of PD-L1 is the key question which largely determines the outcome of the immune checkpoint inhibitors (ICIs) based therapy. The epigenetic mechanism is involved in transcriptional regulation towards PD-L1. However, besides the transcription level, the protein stability of PD-L1 is closely correlated to its function and has drawn more and more attention. In this study, EZH2 inhibition could enhance PD-L1 expression and protein stability, and the deubiquitinase ubiquitin-specific peptidase 22 (USP22) is identified as a key mediator in this process. EZH2 inhibition upregulates the expression of USP22 via canonical mechanism, and upregulated USP22 further stabilize PD-L1. Importantly, a combination of EZH2 inhibitors with anti-PD-1 immune checkpoint blockade therapy could improve the tumor microenvironment, promotes immune cell infiltration, enhances sensitivity to immunotherapy and exerts synergistic anti-cancer effects. In addition, knocking down USP22 could potentially enhance the therapeutic efficacy of EZH2 inhibitor on colon cancer. These findings unveil the novel role of EZH2 inhibitors (EZH2i) in tumor immune evasion by upregulating PD-L1. Although it may be one reason of EZH2i inefficacy due to the fact that it elicits the immune suppressive effect, appropriately utilizing this drawback to arouse PD-L1 expression may convert the tumor into more responsive upon ICI cancer therapy. In addition, the EZH2-USP22-PD-L1 regulatory axis could further facilitating to identify populations sensitive to immunotherapy or provide novel strategy for combined treatment. Therefore, these findings provide valuable insights into the intricate interplay between EZH2 and PD-L1, shedding light on the optimization of combining both immune checkpoint blockade and EZH2 inhibitor based epigenetic therapies to achieve more efficacies and accuracy in cancer treatment.
Citation Format: Jianling Yang, Jiaqi Huang, Qianqian Yin, Lixiang Xue. EZH2 inhibition enhances PD-L1 protein stability through USP22-mediated deubiquitination in 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 3721.
Abstract 3723: Hepatic arterial infusion chemotherapy prolongs patient survival in HCC after atezolizumab and bevacizumab failure
Authors: Sung Pil Soo 
Published: March 2024

Abstract
Background: Atezolizumab/bevacizumab is the first-line chemotherapy for unresectable hepatocellular carcinoma (HCC) patients. In our institute, if the patient is not feasible for or cannot afford the first-line systemic chemotherapy, hepatic artery infusion chemotherapy (HAIC) is proposed and used for treatment The purpose of the study was to compare the prognosis of HAIC treatment in newly diagnosed patients and patients who received HAIC after atezolizumab-bevacizumab treatment failure.
Methods: We retrospectively assessed 49 HCC patients who were treated with HAIC between January 2022 and August 2023. 35 patients were treated with HAIC at initial diagnosis and 14 patients were treated with HAIC after the first line chemotherapy Atezolizumab-bevacizumab combination chemotherapy. We evaluated tumor response, progression free survival (PFS), disease control rate (DCR) and overall survival (OS).
Results: There was a no significant difference in OS and PFS between HCC patients who were treated with HAIC at initial diagnosis and those who were treated after atezolizumab bevacizumab treatment failure. (P value = 0.0770, 0.6993 respectively) In addition, there was no significant difference in the treatment responses. (P=0.4330) Our analysis of the objective response rate (ORR) and disease control rate (DCR) also revealed no significant difference between the two treatment groups. (P=0.247 and 0.829 respectively).
Conclusion: There was no significant difference between the OS and PFS of advanced HCC patients who were treated with HAIC at initial diagnosis and those who were treated with HAIC after atezolizumab bevacizumab treatment failure. Hepatic arterial infusion chemotherapy may prolong patient survival in HCC after atezolizumab and bevacizumab failure.
Citation Format: Pil Soo Sung. Hepatic arterial infusion chemotherapy prolongs patient survival in HCC after atezolizumab and bevacizumab failure [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 3723.
Abstract 3758: Evaluation of breast cancer-derived extracellular vesicles as diagnostic indicator for HER2 status
Authors: Moon Sol , Kim Min Woo , Kim Young , Lee Suji , Lee Hyojung , Kim Joon Ye , Kim Seung Il , Kim Jee Ye 
Published: March 2024

Abstract
HER2-low is a new distinct type of breast cancer that is characterized by low levels of the HER2 protein. As treatment paradigms for HER2-low breast cancer are rapidly evolving with the approval of antibody-drug conjugates, identification of HER2-low breast cancer with more sensitive and reproducible HER2 assays is needed. We aimed to investigate the utility of liquid biopsy in isolating tumor-derived extracellular vesicles (TDEs) for diagnosis of HER2 status. We adopted an affinity-based approach to isolate TDEs and performed CNV analysis of the ERBB2/neu genes using the tumor DNA present in TDEs (etDNA). HER2 status of etDNA had been determined by droplet digital PCR using HER2/EIF2C ratio, a highly accurate method to quantify DNA copy number. In our study, we utilized a variety of breast cancer cell lines categorized as HER2-low (MDA-MB-231, MCF7, ZR-75-1) and HER2-high (MDA-MB-453, BT-474, SK-BR-3) to confirm HER2 expression in extracellular vesicles (EVs) by flow cytometry. This analysis successfully demonstrated that EVs effectively reflect the HER2 status of the tumor cells, evidenced by a strong Pearson correlation coefficient (r=0.987, p&lt;0.001). Further clinical validation was conducted with plasma samples from 22 breast cancer patients. In the clinical study, we observed a significant correlation between the CNV of tumor DNA present in TDEs and the HER2 status of primary tumors (p&lt;0.01). Additionally, the Receiver Operating Characteristic (ROC) analysis yielded an impressive area under the curve (AUC) value of 0.838 (p&lt;0.01), demonstrating a high level of accuracy in differentiating between high and low HER2 groups, with a sensitivity of 55.6% and a specificity of 100%. In summary, we show potential diagnostic tools for real-time, less invasive determination of HER2 status in primary tumors, providing continuous monitoring methods for HER2 status. Although further validation in larger cohorts and prospective studies is needed, our study indicates that TDE analysis could contribute to the assays for identification of the HER2 status in breast cancer patients.
Citation Format: Sol Moon, Min Woo Kim, Young Kim, Suji Lee, Hyojung Lee, Joon Ye Kim, Seung Il Kim, Jee Ye Kim. Evaluation of breast cancer-derived extracellular vesicles as diagnostic indicator for HER2 status [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 3758.
Abstract 3796: Investigating unbiased whole transcriptome high-resolution spatial interactions within tumor masses
Authors: Lee Marie M. , Wilhelmy Julie , Ong Thomas , Wang Wanxin , Yeung Bertrand , Chang Christina , Fan Christina 
Published: March 2024

Abstract
Tumor masses contain a diverse array of cell types, including both normal and tumor cells from different lineages, endothelial cells, and immune cells. Interactions among these cellular constituents and their spatial arrangements play a pivotal role in tumor development, progression, and metastasis. While single-cell analysis has provided valuable insights regarding the dissociated cellular composition of tumors, it falls short in elucidating the complex interplay of cell-cell interactions and spatial relationships that may drive tumor cellular behavior and gene expression.
We used the Curio Seeker Spatial Mapping Kits to uncover those spatial relationships in human tumor samples. The method captured whole transcriptomes and preserved the spatial locations of tumor cells, infiltrating immune cells, and normal cells by self segregating gene expression signatures and unbiased clustering. Amongst other findings by using Curio Seeker, we identified areas of immune cell infiltrates that were devoid of tumor cells, signifying zones of potential anti-tumor response.
The high spatial resolution, continuous gene expression maps from the Curio Seeker Spatial Mapping Kits reveal spatial interactions between different cellular populations that enable researchers to better understand how the interplay between tumor cell types and their cellular neighborhoods affect gene expression and tumor cell behavior.
Citation Format: Marie M. Lee, Julie Wilhelmy, Thomas Ong, Wanxin Wang, Bertrand Yeung, Christina Chang, Christina Fan. Investigating unbiased whole transcriptome high-resolution spatial interactions within tumor masses [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 3796.
Abstract 3805: Intestinal microbiome with chemotherapy response and RAS mutation in patients with advanced or metastatic colorectal cancer: a pilot, exploratory study
Authors: Kim Jwa Hoon , Kim Boyeon , Lee Soohyeon 
Published: March 2024

Abstract
Intestinal microbiomes interact with the tumor microenvironment, participating in inflammation and immune regulation, and are associated with the response to anticancer therapy. However, there has been limited research exploring the relationship between changes in the microbiome and treatment response in patients with metastatic colorectal cancer (mCRC) during chemotherapy and radiation therapy.This study included all 15 patients with mCRC treated with first-line systemic therapy between October 2021 and February 2023. We conducted 16S rRNA sequencing on baseline stool samples and investigated the association of intestinal microbiome with chemotherapy response and RAS mutation. The QIIME2 and R packages were used for analysis. As a results, Median age was 61 years (range, 35-73), and there were 8 patients with RAS-mutated mCRC. All patients were treated with first-line systemic therapy; FOLFOX (5-fluorouracil and oxaliplatin)-based (n=13) and FOLFIRI (5-fluorouracil and irinotecan)-based chemotherapy (n=2). Of them, 2 patients received short-course radiotherapy (ScRTx) to primary tumor before systemic chemotherapy, where pre- and post-ScRTx stool samples were collected. Among 15 patients, 9 patients (60%) achieved responses. Non-responders tend to exhibit higher alpha diversity (Chao1, Observed ASV) compared to responders. Firmicutes, Lactobacillus, Faecalibacterium, and the [Luminococcus]_gauvreauii_group were more prevalent in responders, whereas Bacteroidota, Prevotella, DTU089, Alistipes, Christensenellaceae_R-7_group, and Porphyromonas in non-responders. Despite no statistical significance, alpha diversity decreased in post-ScRTx compared to pre-ScRTx samples. Akkermansia, Prevotella, and Peptostreptococcus were more prevalent in the post-ScRTx compared to pre-ScRTx samples. Regarding the association of intestinal microbiome with RAS mutation, Bray curtis and weighted unifrac analyses revealed significant differences in beta diversity; higher incidence of Faecalibacterium, Lactobacillus, Prevotella, Anaerofilum, and UCG-005 in the RAS-wild type mCRC, while Bacteroides, Collinsella, Holdemanella, and Anaerostipes in RAS-mutated mCRC.This pilot study suggests the prognostic value of gut microbiomes and its association with RAS mutation in patients with mCRC treated with first line systemic therapy. A microbial functional study with immune cytokine change is planned to confirm these findings in future.
Citation Format: Jwa Hoon Kim, Boyeon Kim, Soohyeon Lee. Intestinal microbiome with chemotherapy response and RAS mutation in patients with advanced or metastatic colorectal cancer: a pilot, exploratory study [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 3805.
Abstract 3811: Impact of antiviral treatment status on risk of extrahepatic cancers in patients with chronic hepatitis C
Authors: Tao Menghua , Li Jia , Wu Trueman , Gordon Stuart C. , Rupp Loralee B. , Trudeau Sheri , Holmberg Scott D. , Moorman Anne C. , Spradling Philip R. , Teshale Eyasu H. , Schmidt Mark A. , Daida Yihe G. , Lu Mei 
Published: March 2024

Abstract
Background: Eradiation of hepatitis C virus (HCV) infection has been shown to reduce risk of liver cancer among HCV patients; however, there has been spare data on the effect of antiviral treatment on the risk of extrahepatic cancers. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we investigated whether antiviral therapy impacts the risk of extrahepatic cancers among patients with HCV.
Methods: 17,485 HCV patients were included in the study, and they were followed until incidence of cancer including lung cancer, non-Hodgkin lymphoma (NHL), breast cancer or prostate cancer, death, or last follow-up. An extended landmark modeling approach was considered, which included time-varying covariates and propensity score justification for treatment selection bias and used generalized estimating equations (GEE) with a link function as multinominal distribution for a discrete time-to-event data. Death was considered a competing risk.
Results: Compared to untreated patients, patients with HCV treatment had significantly lower risk of lung cancer for direct-acting antiviral (DAA) treatment (hazard ratio (HR) = 0.47, 95% CI, 0.30-0.72) and for interferon-based treatment (IFN) (HR = 0.33, 95% CI, 0.20-0.50). The risk of NHL was only reduced among patients receiving DAA treatment. There were no significant associations between HCV treatment and risks of breast and prostate cancer.
Conclusion: Both DAA and IFN antiviral treatment independently reduce the risk of lung cancer, while the protective association with NHL was limited among HCV patients with DAA treatment. Our findings support the importance of timely initiation antiviral therapy in chronic HCV-infected patients.
Citation Format: Menghua Tao, Jia Li, Trueman Wu, Stuart C. Gordon, Loralee B. Rupp, Sheri Trudeau, Scott D. Holmberg, Anne C. Moorman, Philip R. Spradling, Eyasu H. Teshale, Mark A. Schmidt, Yihe G. Daida, Mei Lu. Impact of antiviral treatment status on risk of extrahepatic cancers in patients with chronic hepatitis C [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 3811.
Abstract 3848: Comprehensive protein analysis to identify the proteins responsible for sarcopenia and their impact on antitumor immunotherapy in non-small cell lung cancer
Authors: Masuda Takaaki , Watanabe Satoshi , Wakabayashi Tomoya , Tanaka Susumu , Shono Kunihiro , Suzuki Ryo , Sekiya Tomoki , Yanagimura Naohiro , Arita Masashi , Ohtsubo Aya , Tanaka Tomohiro , Nozaki Koichiro , Saida Yu , Hokari Satoshi , Kondo Rie , Shima Kenjiro , Kimura Yosuke , Aoki Nobumasa , Ohshima Yasuyoshi , Koya Toshiyuki , Sakai Kazuko , Nishio Kazuto , Yamazaki Motohiko , Ishikawa Hiroyuki , Kikuchi Toshiaki 
Published: March 2024

Abstract
Background: Previous retrospective studies have shown that sarcopenia (Sar) is associated with poor outcome in cancer patients (pts) receiving immune checkpoint inhibitors (ICIs). We conducted a prospective study to determine whether Sar-related proteins induce Sar and reduce the efficacy of ICI.
Method: Non-small cell lung cancer (NSCLC) pts receiving ICI as first-line treatment at Niigata University Medical and Dental Hospital were eligible. Sar was diagnosed with physical performance and skeletal muscle mass. Comprehensive protein analysis of pre-treatment blood samples was performed to identify factors that correlate with muscle loss and ICI effects.
Result: 41 patients were enrolled from October 2019 through August 2022. PFS for Sar was 4.6 months, 6.7 months for Pre-Sar, and 16.7 months for Non-Sar (P=0.0028). OS for Sar was not reached, 15.7 months for Pre-Sar, and not reached for Non-Sar (P=0.0014). Leptin, IL-1β, IL-12, and Pentraxin 3 were significantly correlated with loss of muscle mass. In contrast, leptin, insulin, IGF-1, GDF-8, Activin A, IL-2Ra, IL-8, MMP-3, osteopontin, and Pentraxin-3 were significantly associated with poor OS. Pentraxin 3 and leptin were associated with both the effectiveness of immunotherapy and sarcopenia. A multivariate analysis that considered factors commonly associated with the effectiveness of immunotherapy, including age, PD-L1 expression rate, and neutrophil-lymphocyte ratio, Pentraxin 3 was determined to be an independent prognostic factor.
Conclusion: This study indicated that Sar-related proteins and inflammatory cytokines are involved in the development of Sar and ICI efficacy.
Citation Format: Takaaki Masuda, Satoshi Watanabe, Tomoya Wakabayashi, Susumu Tanaka, Kunihiro Shono, Ryo Suzuki, Tomoki Sekiya, Naohiro Yanagimura, Masashi Arita, Aya Ohtsubo, Tomohiro Tanaka, Koichiro Nozaki, Yu Saida, Satoshi Hokari, Rie Kondo, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Kazuko Sakai, Kazuto Nishio, Motohiko Yamazaki, Hiroyuki Ishikawa, Toshiaki Kikuchi. Comprehensive protein analysis to identify the proteins responsible for sarcopenia and their impact on antitumor immunotherapy 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 3848.
Abstract 3860: Characterizing peripheral immune correlates of tumor response in breast cancer patients immunized with the P10s-PADRE vaccine
Authors: Jousheghany Fariba , Lee John P. , Nounamo Bernice , Raj Vinay , Faulkner Jennifer L. , Siegel Eric , Makhoul Issam , Kieber-Emmons Thomas , Monzavi-Karbassi Behjatolah 
Published: March 2024

Abstract
Introduction: We demonstrated that vaccination of HR+/HER2− breast cancer subjects with P10s-PADRE cancer vaccine in combination with standard-of-care chemotherapy led to generation of antibodies (Ab), activation of Natural Killer (NK) and T cells, increases in IFNγ and TNFα, and increases in TILs and stromal CD3+ T cells. The current study was conducted to assess the vaccine's efficacy, particularly focusing on tumor shrinkage and pathologic Complete Response (pCR). Additionally, it aims to explore the association of specific peripheral-blood immune responses, such as antibody levels and NK and T-cell activation, with pCR and objective reduction in primary tumor size.
Methods: Blood samples collected at baseline and after treatment of at least 25 subjects were used in characterization of immune responses. Serum and plasma samples were used in ELISA, cytokine, and glycan-array assays to measure anti-peptide and anti-glycan antibodies and blood-cytokine levels. Peripheral blood mononuclear cells (PBMCs) were interrogated by RNA-seq, flow cytometry, and ELISpot assays.
Results: We observed that high levels of anti-peptide and anti-GD2 antibody responses correlated with pCR. Ab response was positively correlated with differential expression of CD56, GZMA, IFNγ, NKp46, and CD8b, among which GZMA and NKp46 showed a statistically significant association. Vaccine-induced functional cellular immune responses (measured by differential expression of IFNγ, GZMA, CD8, CD69, NKp46, CD56, and PRF1) correlated with reduction of primary tumor size. We also observed substantial differences among immune responders vs non-responders in immune gene expression and in cytokine production in post-immune PBMCs after specific and polyclonal stimulation.
Conclusions: The data suggest that immunization of HR+/HER2− breast cancer patients with P10s-PADRE in combination with chemotherapy leads to both humoral and cellular immune responses. While induction of a robust antibody response is a good marker for potential clinical efficacy, vaccine-associated increases of the ratio of CD8+ cells and the expression of CD69, CD8b, GZMA, IFNγ, NKp46, and PRF1 seem to serve as additional efficacy indicators. Future studies are underway to validate these findings and establish reliable prognostic biomarkers.
Citation Format: Fariba Jousheghany, John P. Lee, Bernice Nounamo, Vinay Raj, Jennifer L. Faulkner, Eric Siegel, Issam Makhoul, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi. Characterizing peripheral immune correlates of tumor response in breast cancer patients immunized with the P10s-PADRE 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 3860.
Abstract 3872: Multi-ancestral origins of colorectal lesionsMulti-ancestral origins of colorectal lesions
Authors: Schenck Ryan O. , Khan Aziz , Horning Aaron , Esplin Edward D. , Van Egeren Debra ,   HTAN–FAP Consortium, Greenleaf William , Ford James M. , Snyder Michael P. , Curtis Christina 
Published: March 2024

Abstract
The widely accepted paradigm that cancer initiation is a monoclonal event has not been definitively resolved. In sporadic cancers this is due to the requirement for longitudinal sampling to study this occult process, which occurs over years to decades. Individuals with familial adenomatous polyposis (FAP) possess a germline APC mutation, leading to hundreds of colonic polyps in adolescence and a 100% lifetime risk of colorectal cancer. Resected colons from FAP patients contain normal mucosa, benign and dysplastic polyps that embed the natural history of colorectal tumorigenesis at different points of malignant progression. Through genome sequencing of 127 independent polyps or mucosa samples from six FAP patients, we characterized the genomic landscape, relative timing of somatic alterations, and clonal dynamics in normal, dysplastic, and invasive colon tissue. Comparison with multi-region sequencing data from FAP patients and sporadic colorectal adenomas and carcinomas indicates similar molecular profiles, with canonical cancer driver genes present across benign and dysplastic premalignant lesions and shared mutational orders. Pairwise sample comparisons and phylogenetic reconstructions revealed extensive heterogeneity and subclonal sharing within a patient’s benign and dysplastic lesions, irrespective of location in the colon. These data imply that polyps were initiated from multiple cells from distinct lineages whose most recent common ancestor arose during development. We corroborate these findings using a mechanistic mathematical model, which infers polyclonality in 100% of benign and 83% of dysplastic samples. Based on these findings, we propose a conceptual model of the multi-ancestral origin of intestinal malignancies.
Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Debra Van Egeren, HTAN–FAP Consortium, William Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. Multi-ancestral origins of colorectal lesionsMulti-ancestral origins of colorectal lesions [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 3872.