bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2261: A scalable comparison of tumor immune atlases
Authors: Yang Jing , Liu Qi , Shyr Yu 
Published: March 2024

Abstract
Large single-cell atlases can serve as references for the analysis of smaller-scale studies. However, there are strong biases among atlases due to their varying sample sources, conditions, cell type annotation strategies and resolutions. Selecting appropriate atlas for future or smaller-scale studies is complicated due to unclear understanding of atlases, that limits the future or smaller-scale studies take advantage of the wealth of data that such atlases provide. For example, the tumor-infiltrating immune cell atlases including pan-cancer and cancer type-specific atlases provide comprehensive profiling of immune cells, which desperately facilitates future single-cell studies. However, lack of a comprehensive assessment and comparison of tumor immune cell atlases with standardized benchmarks blocked the application of the most appropriate atlas for smaller-scale study. In this study, we compared pan-cancer immune cell atlases including TICA, pan-cancer T cells and pan-cancer blueprint atlases, and cancer-type specific immune cell atlases containing ABTC, HCC and STAD atlases. We quantified the correlations of cell types and observed similar heterogeneity among atlases and unique immune cell populations in TICA as well. Then, we assessed the performance of atlases on accurately annotating immune cell types in the widely studied PBMC datasets—in which cell types were well annotated. Comparative analysis revealed the complementarity within atlases on mapping success, accuracy, clustering, annotatability and stability by benchmarking reference-based populations to reference-free de novo clustering on real immunotherapy datasets. We identified potential indicators of immune response and found that reference-based populations outperformed reference-free clusters in recognizing immunotherapy-related cell states. Our study can be easily extended to future atlases.
Citation Format: Jing Yang, Qi Liu, Yu Shyr. A scalable comparison of tumor immune atlases [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 2261.
Abstract 2276: Comprehensive analysis of the genomic landscape of thyroid cancer
Authors: Im SooHyun , Park Jong-Lyul , Kim Jae-Yoon , Jung Chan-Kwon , Kim Seon-Young 
Published: March 2024

Abstract
Thyroid cancer, the most common endocrine malignancy, has a high incidence worldwide. Meanwhile, the incidence of thyroid cancer ranks first in Korea. To assess the possible influence of ethnicity on the molecular profile of thyroid cancer, we compared the genomic features of South Korean thyroid cancer with European thyroid cancer. In this study, we performed whole genome sequencing profiling (WGS) for 459 Korean thyroid cancer patients, including papillary thyroid carcinoma (PTC, n = 274), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP, n =18), follicular thyroid carcinoma (FTC, n = 16), follicular thyroid adenoma (FTA, n = 63), Hürthle cell adenoma (HCA, n = 22), and invasive encapsulated follicular variant papillary thyroid carcinoma (IEFVPTC, n = 19). We assessed the single nucleotide variant (SNV) and insertions and deletions using Mutect2, Varscan2, and Strelka2. For mutation signature and copy number alterations analysis, we used the Maftools and GISTIC2.0 packages, respectively. Our results revealed that most somatic mutations were similar between the Korean thyroid cancer dataset and the cancer genome atlas program (TCGA). However, the Korean cohort (1%) had a much lower NRAS mutation frequency than the TCGA cohort (8%). Mutation signature analysis showed that SBS6 and SBS2 were highly associated with the TCGA and Korean cohort. SBS6 is related to defective DNA mismatch repair, and SBS2 is characterized predominantly by CC &gt; TT doublet base substitutions. In addition, we identified the NIFTP-specific somatic mutations such as KEAP1 and ZFP36L2. This study presents insights into the genomic landscape of Korean thyroid cancer and reveals some similarities and differences with European thyroid cancer at the molecular level.
Citation Format: SooHyun Im, Jong-Lyul Park, Jae-Yoon Kim, Chan-Kwon Jung, Seon-Young Kim. Comprehensive analysis of the genomic landscape of thyroid 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 2276.
Abstract 2325: NUWA-ms: A network-based method to infer quantification of missing proteins using multi-cohort proteomics profiles
Authors: Cao Lihua , Xie Yuhao , Chen Jiale , Wang Man , Zhao Tingting , Yang Heli , Du Yang , Yang Yang , Bu Zhaode , Ji Jiafu , Wu Jianmin 
Published: March 2024

Abstract
Although mass spectrometry is powerful for proteomic quantification, the inherent issue of missing values remains a significant challenge. We found a prevalent lack of quantification of valuable proteins (e.g., immune cell markers and drug targets) in published datasets, limiting the functional utilities of quantitative proteomic profiles. This was exemplified by the substantial lack of quantification of immune cell marker, which impede the dissection of tissue-infiltrating immune cells by deconvolution analysis of cancer proteomic profiles. Thus, we introduce a network-based method NUWA-ms for robust abundance inference of missing proteins using multi-cohort proteomic profiles. By evaluating 561 tumors with paired proteomic and transcriptomic profiles, a significant improvement of deconvolution performance was shown with the aid of NUWA-ms. This was further validated by the comparison between scRNA-seq and proteomic analyses of a same gastric cancer tumor tissue. NUWA-ms applications to cancer proteomic profiles facilitated the inference of CD8+ T cell markers and effector proteins, enabling the associations of CD8+ T cell infiltration with MSI status in colorectal cancer and anti-PD-1 therapy response in melanoma. These findings demonstrated the utilities of NUWA-ms in depicting infiltrating lymphocytes in the tumor microenvironment using proteomic profiles. Furthermore, based on the proteomic profiles of six patient-derived tumor organoids (PDOs), NUWA-ms application helped identifying PDOs sensitive to a targeted therapeutic agent including the ones neglected by the raw MS quantification, and aided in revealing the resistant mechanism. Together, NUWA-ms could enable a robust inference of protein abundance, to help identifying protein biomarkers and therapeutic targets for cancer and other complex diseases.
Citation Format: Lihua Cao, Yuhao Xie, Jiale Chen, Man Wang, Tingting Zhao, Heli Yang, Yang Du, Yang Yang, Zhaode Bu, Jiafu Ji, Jianmin Wu. NUWA-ms: A network-based method to infer quantification of missing proteins using multi-cohort proteomics profiles [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 2325.
Abstract 2379: The bispecific antibody KA-3007 against B7H3 and CD28 enhances T cell activation in solid tumors
Authors: Wu Guojin , Guo Zhengcheng , Peng Hao , Hao Feng , He Feng , Ning Jinying 
Published: March 2024

Abstract
Immunotherapy, revolutionizing the treatment of advanced solid tumors by blocking PD1 signaling, faces challenges as most cancers remain unresponsive to anti-PD-1 therapy. CD28, a key immune co-stimulatory receptor on T cells, often lacks ligands expressed on tumor cells. B7H3 is highly expressed in various solid tumors. In this study, we developed a bispecific antibody (BsAb) named KA-3007, targeting B7H3 and human CD28 to activate T cells in the tumor microenvironment. KA-3007, featuring an identical light chain, was developed using our common light chain bispecific antibody discovery platform with knob-into-hole technology. This BsAb is in regular IgG1 format with mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. Its two Fabs bind to B7H3 with high affinity and CD28 with relatively low affinity. Co-culturing T cells with tumor cells expressing B7H3 enhances T cell activation. In PBMC humanized immunodeficient mouse tumor models, KA-3007 effectively suppresses the growth of NCI-H292 tumors, with or without a PD1 antagonist antibody. Furthermore, this antibody exhibits a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of KA-3007 with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and it shows neither aggregation nor degradation. In conclusion, the BsAb KA-3007, developed with our common light chain antibody discovery platform, emerges as a promising pre-clinical candidate drug for the treatment of solid cancers.
Citation Format: Guojin Wu, Zhengcheng Guo, Hao Peng, Feng Hao, Feng He, Jinying Ning. The bispecific antibody KA-3007 against B7H3 and CD28 enhances T cell activation in solid 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 2379.
Abstract 2477: Selective IL-21 and IFN-alpha immunocytokines engineered using the AlphaSeq platform
Authors: Lin Charles , Shikany Colleen , Homad Leah , Fint Jessica , Bansal Ruchi , Goodnight Davis , Adamo Jeff , Van Citters Danielle , Swanson Ryan , Lopez Randolph 
Published: March 2024

Abstract
Although cytokine therapies have demonstrated curative effects in some cancer patients, clinical use remains limited due to undesired toxicity profiles accompanying systemic administration. Next generation cytokine approaches include conditional signaling focused on sites of interest, such as the tumor microenvironment or specific immune cell populations. Here, we share a novel approach for generating detuned cytokine therapeutic candidates using the AlphaSeq platform, which involves the re-engineering of yeast agglutination and mating to quantitatively measure protein-protein interactions at a library-on-library scale. Engineering interferon-alpha (IFNα) and interleukin-21 (IL-21), we show how AlphaSeq measures cytokine-receptor interactions and identifies cytokine variants with a broad range of affinities. A saturated mutational library was created for IFNα and IL-21and subsequently screened against a second library consisting of human IFNAR2 or human IL-21R, species orthologs and off-target receptors. AlphaSeq enabled identification of hundreds of detuned IFNα and IL-21 variants against both human and mouse receptors in parallel assays. Cytokine variants with lower affinity than parental IFNα or IL-21 were recombinantly expressed as Fc fusion proteins to orthogonally measure affinity with biolayer interferometry and characterize potency with an in vitro human PBMC phosflow assay, which showed strong correlation with AlphaSeq affinity measurements. Finally, detuned cytokine candidates were fused to anti-CD8 and other localizing antibodies to demonstrate cell population-specific signaling. Candidate molecules showed 1000-fold or greater potency in the targeted cell population than non-targeted populations. Our results show the AlphaSeq platform can accurately quantitate thousands of cytokine variant affinities simultaneously against multiple relevant receptors, enabling the selection of candidate immunocytokine antibody fusion proteins with targeted cell biased signaling. AlphaSeq’s rapid, comprehensive affinity determination is being used to develop clinically relevant IFNα and IL-21 therapeutic immunocytokines with accompanying preclinical data.
Citation Format: Charles Lin, Colleen Shikany, Leah Homad, Jessica Fint, Ruchi Bansal, Davis Goodnight, Jeff Adamo, Danielle Van Citters, Ryan Swanson, Randolph Lopez. Selective IL-21 and IFN-alpha immunocytokines engineered using the AlphaSeq platform [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 2477.
Abstract 2503: The role of APOBEC in early stage-EGFR mutant non-small cell lung cancer
Authors: Jung Hyun Ae , Lim Jinyeong , Choi Yoon-La , Park Sehhoon , Sun Jong-Mu , Ahn Myung-Ju , Lee Se-Hoon 
Published: March 2024

Abstract
Background: The APOBEC family of zinc-coordinating enzymes converts cytosines to uracils in single-strand DNA. APOBEC plays a crucial role in the mutation process of non-small cell lung cancer (NSCLC) and is essential for both adaptive and innate immune responses. This study aims to evaluate the role of the APOBEC mutation signature in early-stage non-small cell lung cancer (NSCLC).
Methods: We conducted whole-exome sequencing and whole-transcriptome sequencing using fresh tissue or formalin-fixed paraffin-embedded samples from 100 patients diagnosed with pathologic stage II-IIIA non-squamous NSCLC, all of whom underwent complete resection between January 2014 and December 2020 at Samsung Medical Center. This study aimed to assess the impact of APOBEC enrichment on disease-free survival (DFS), progression-free survival (PFS) of EGFR-TKI, and overall survival following recurrence.
Results: Median follow-up duration was 58.2 months (range, 11.3-141.1). Of the patients, 74% were never-smokers, and 52% had stage III disease. Among the 100 patients, 18 (18%) exhibited APOBEC enrichment (≥ 2). The median RFS was 25.2 months (95% CI, 17.3-33.2). Notably, APOBEC enrichment did not show a significant association with DFS (P=0.14). Among the 76 patients who experienced radiological recurrence, 69 received EGFR-TKI as first-line treatment. The median PFS for EGFR-TKI was 22.9 months (95% CI, 13.0-32.8). However, within this group, patients with APOBEC enrichment showed a shorter PFS compared to those without APOBEC enrichment (8.1 months vs. 24.6 months, P=0.014). In multivariate analysis, poor PFS of EGFR-TKI was associated with the type of EGFR mutation (L858R vs. exon 19 deletion, HR=1.9, P=0.04), TP53 mutation (mutation vs. wild type, HR=2.1, P=0.03), and APOBEC enrichment (≥ 2 vs. &lt;2, HR=2.2, P=0.02). Overall survival from the starting EGFR-TKI was 61.1 months and 21.7 months for patients with APOBEC enrichment or patients without APOBEC enrichment, respectively (P=0.027).
Conclusions: APOBEC mutation signature may be presented at initial diagnosis of early-stage EGFR mutant NSCLC and it was associated with poor PFS of EGFR-TKI and overall survival.
Citation Format: Hyun Ae Jung, Jinyeong Lim, Yoon-La Choi, Sehhoon Park, Jong-Mu Sun, Myung-Ju Ahn, Se-Hoon Lee. The role of APOBEC in early stage-EGFR mutant 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 2503.
Abstract 2517: The amplification of TPX2 is a potential biomarker of oxaliplatin-sensitivity of colorectal cancers (CRCs) with CIN phenotype
Authors: Ueno Shohei , Isobe Taichi , Taguchi Ryosuke , Tsuchihashi Kenji , Akashi Koichi , Baba Eishi 
Published: March 2024

Abstract
The amplification of Chr20q11.21 harboring TPX2 gene is the most frequent copy number alteration among the cases of colorectal cancers (CRCs), especially left-sided ones. We retrospectively examined 2828 cases of CRC patients who took cancer-genome panel tests in Japan between June 2019 and November 2022. The time to first-line treatment failure was longer with regimen with oxaliplatin than with those with irinotecan in CRC patients with Chr20q11,21 amplification (12.2 versus 9.2 months, p=0.0481). Oxaliplatin induces double-strand breaks (DSBs) and then cellular apoptosis. A key event of the DNA damage response to DSBs for cellular survival is the extensive phosphorylation of Ser139 of Histone H2AX adjacent to the chromosomal break. TPX2 whose gene resides in Chr20q11,21 has been reported to repress the phosphorylation of H2AX upon ionizing radiation. The purpose of this study is to identify the relationship between the amplification of TPX2 and oxaliplatin sensitivity in human CRCs. The knockdown of TPX2 decreased the oxaliplatin-susceptibility of COLO320 and Caco-2, CIN phenotype CRC cell lines which highly expressed TPX2. However, TPX2 knockdown did not reduce the oxaliplatin sensitivity of HCT-116, an MSI phenotype CRC cell line with low-level of TPX2 expression. The knockdown of TPX2 in CIN phenotype CRC cells, not in the MSI phenotype CRC cells, enhanced the phosphorylation of H2AX upon the DNA-damage induced by oxaliplatin. These findings suggest that amplification of TPX2 contributes to the oxaliplatin-susceptibility of CRCs with CIN phenotype through DNA repair machinery.
Citation Format: Shohei Ueno, Taichi Isobe, Ryosuke Taguchi, Kenji Tsuchihashi, Koichi Akashi, Eishi Baba. The amplification of TPX2 is a potential biomarker of oxaliplatin-sensitivity of colorectal cancers (CRCs) with CIN phenotype [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 2517.
Abstract 2527: PD-L1 regulation by Dual Oxygenase 2 (DUOX2), a reactive oxygen species (ROS) producing enzyme in gastric cancers
Authors: Carrier France , Martins Mariana B. 
Published: March 2024

Abstract
Immune checkpoint inhibitors have shown outstanding activities in some cancers, but their efficacy is rather variable with limited long-term response in most patients while others do not respond well or even develop resistances. The oxidative state of the tumor and its microenvironment plays a critical role in this response and highlights the importance of better understanding the role of redox enzymes in response to immunotherapy. In fact, Reactive Oxygen Species (ROS) effectors can either up or down regulate PD-L1 expression depending on their targets and mechanisms of action. Our data indicate that DUOX2, an NADPH enzyme involved in the production of H2O2, is expressed in about forty percent of human gastric cancers and is significantly increased in esophageal cancers. Moreover, DUOX2 expression in human gastric and esophageal cancer cells corresponds to down regulation of the immune checkpoint PD-L1. Conversely, down regulation of DUOX2 increases PD-L1, HIF-1α and c-Myc expression in these cells. To better understand the role of DUOX2 in the production of ROS and how it interferes with the expressions of HIF-1α and PD-L1, we also evaluated its effects on the ROS scavenger glutathione (GSH) and the ROS generating Ceramide in cells expressing or not DUOX2. The down regulation of DUOX2 reduced by more than half Ceramide levels and significantly increased GSH levels. This is consistent with the known effect of H2O2 on Ceramide generation through sphingomyelin hydrolysis and H2O2 inhibitory effect on HIF-1α binding and accumulation of HIF-1α protein. Because HIF-1α is a known regulator of PD-L1, DUOX2 expression on some tumors could thus interfere with PD-L1 expression through generation of H2O2. Moreover, because HIF-1α and PD-L1 expression contribute to radio-resistance, DUOX2 expression could sensitize cancer cells to radiation therapy. On the other hand, tumors lacking DUOX2 expression would be expected to be more sensitive to immunotherapy targeting PD-1 and/or PD-L1. DUOX2 expression thus appears to hold significant potential as a valuable biomarker to guide therapeutic decisions regarding radiation or immuno-therapy.
Citation Format: France Carrier, Mariana B. Martins. PD-L1 regulation by Dual Oxygenase 2 (DUOX2), a reactive oxygen species (ROS) producing enzyme in gastric 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 2527.
Abstract 2528: Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: A retrospective cohort study
Authors: Yu Pengfei , Ding Guangyu , Huang Xingmao , Wang Chenxuan , Fang Jingquan , Huang Ling , Ye Zeyao , Xu Qi , Wu Xiaoying , Yan Junrong , Ou Qiuxiang , Tang Haimeng , Du Yian , Cheng Xiangdong 
Published: March 2024

Abstract
Background: Patients with peritoneal metastasis (PM) from gastric cancer (GC) exhibit poor prognosis. Chemoimmunotherapy offers promising clinical benefits; however, its efficacy and predictive biomarkers in a conversion therapy setting remain unclear. We aimed to retrospectively evaluate chemoimmunotherapy efficacy in a conversion therapy setting for GC patients with PM and establish a prediction model for assessing clinical benefits.
Methods: A retrospective evaluation of clinical outcomes encompassed 55 GC patients with PM who underwent chemoimmunotherapy in a conversion therapy setting. Baseline PM specimens were collected for genomic and transcriptomic profiling. Clinicopathological factors, gene signatures, and tumor immune microenvironment were evaluated to identify predictive markers and develop a prediction model.
Results: Chemoimmunotherapy achieved a 41.8% objective response rate and 72.4% R0 resection rate in GC patients with PM. Patients with conversion surgery showed better overall survival (OS) than those without the surgery (median OS: not reached vs 7.82m, P&lt;0.0001). Responders to chemoimmunotherapy showed higher ERBB2 and ERBB3 mutation frequencies, CTLA4 and HLA-DQB1 expression, and CD8+ T cell infiltration, but lower CDH1 mutation and naïve CD4+ T cell infiltration, compared to non-responders. A prediction model was established integrating CDH1 and ERBB3 mutations, HLA-DQB1 expression, and naïve CD4+ T cell infiltration (AUC=0.918, 95%CI: 0.846-0.991), which were validated using an independent external cohort (AUC=0.785, 95%CI: 0.637-0.933).
Conclusion: Our study comprehensively evaluated clinicopathological, genomic, and immune features and developed a novel prediction model, providing a rational basis for the selection of GC patients with PM for chemoimmunotherapy-involved conversion therapy.
Citation Format: Pengfei Yu, Guangyu Ding, Xingmao Huang, Chenxuan Wang, Jingquan Fang, Ling Huang, Zeyao Ye, Qi Xu, Xiaoying Wu, Junrong Yan, Qiuxiang Ou, Haimeng Tang, Yian Du, Xiangdong Cheng. Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: A retrospective cohort 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 2528.