bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3740: Tusamitamab ravtansine induces immunogenic cell death and synergizes with anti-PD-1 or anti-PD-L1 antibody combination in solid tumor
Authors: Nicolazzi Celine , Lefebvre Anne-Marie , Moindrot Nicolas , Larois Christelle , Classe Marion , Sidhu Sukhvinder 
Published: March 2024

Abstract
Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC) targeted to carcino-embryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivering DM4, a maytansinoid cytotoxic. CEACAM5 is highly expressed in several tumor types, including non-squamous non-small cell lung cancer (NSQ NSCLC). It is currently being evaluated in patients with advanced CEACAM5-positive NSQ NSCLC, in a phase II study in combination with pembrolizumab, and a phase III trial as single agent in comparison with docetaxel. Preclinical investigations were performed to determine whether SAR408701 could be beneficially combined with immune checkpoint inhibitors. We, first, demonstrated that the tusamitamab ravtansine payload, DM4, is able to induce robust immunogenic cell death (ICD) using an in vivo vaccination assay. In this assay, immunocompetent mice were “vaccinated” by DM4-treated CT26 cells and then later rechallenged with CT26 tumor cells. Tumor rejection was observed in more than 50% of “vaccinated” mice. The ICD was characterized by the expression or release of danger-associated molecular patterns (DAMPs), and we observed DAMP modulation such as calreticulin (CRT) exposure at the cell surface of dying tumor cells, and the release of the High-Mobility Group Box 1 (HMGB1) in the extracellular space by CT26 cells in response to DM4 treatment. We also showed that DM4-treated CT26 tumor cells implanted into mice or SAR408701 treatment of MC38 tumor-bearing mice induced an elevation of plasmatic level of murine IL-6 and INFγ, revealing potential antitumor immunity modulation by the ADC and its payload. Immunohistochemistry analysis of MC38 tumors also revealed that tusamitamab ravtansine treatment induced a dose-dependent increase of CD8 T-cell infiltration in tumors correlating to dose-dependent efficacy. Finally, tusamitamab ravtansine was combined with immune checkpoint inhibitors (ICIs) in immunocompetent mice bearing MC38 tumor model. In this model, the combination of tusamitamab ravtansine with anti-PD-1 or anti-PD-L1 antibody led to complete response and, even, tumor-free survivors at 120 days post tumor implantation while single agents were inactive or transiently active. In summary, these preclinical data show that tusamitamab ravtansine could be beneficially combined with immune checkpoint and strongly support their evaluation in clinical development.
Citation Format: Celine Nicolazzi, Anne-Marie Lefebvre, Nicolas Moindrot, Christelle Larois, Marion Classe, Sukhvinder Sidhu. Tusamitamab ravtansine induces immunogenic cell death and synergizes with anti-PD-1 or anti-PD-L1 antibody combination in solid tumor [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 3740.
Abstract 3799: Spatial biomarker prediction in papillary renal cell carcinoma using artificial intelligence-based immunofluorescent inference
Authors: Brewer Jared , Vento Joseph , Haake Scott , Reddy Anupama 
Published: March 2024

Abstract
Papillary renal cell carcinoma (pRCC) accounts for ~15-20% of the global burden for kidney cancers but still lacks effective mechanisms to predict patient responses to therapeutic intervention. Existing therapies targeting kidney cancers (anti-angiogenesis and immunotherapy) intimately involve the tumor microenvironment in their mechanism of action. However, the role of the physical organization of the tumor in determining therapeutic efficacy remains unknown. Previous efforts have utilized transcriptional profiling to stratify patients into treatment categories but here we propose to leverage artificial neural networks (“AI”) to infer the expression of marker genes for particular cell types of interest based on ubiquitously expressed immunofluorescence channels, unstained brightfield images, and hematoxylin and eosin (H&E) stained images. We have developed AI models that are capable of the prediction of a range of relevant cell types based on the expression profile of DAPI, type IV collagen, and integrin beta-1, including endothelial cells, T cells, macrophages and other cell types. This work applies an AI model class known as generative adversarial networks (GANs) to produce photo-realistic simulated immunofluorescence images based on the input channels. This approach may allow us to accurately predict complex multiplex immunofluorescence (mIF) images from simpler, more routine histological methods, greatly reducing the cost burden required to profile histopathology images for cell types of interest. Our previous work identified a number of interesting cell-cell association clusters correlated with patient prognosis and this extension of that previous work aims to allow for the prediction of these interactions while obviating the need to perform the original, costly multiplex immunofluorescence assay or even a more reduced immunofluorescence staining panel which may still be out of reach for many clinical pathology labs and the interpretation of which may be challenging. By simplifying and increasing the availability of predictive AI models for digital pathology, we hope to further develop and apply predictive biomarkers for patient prognosis and treatment response in papillary renal cell carcinoma.
Citation Format: Jared Brewer, Joseph Vento, Scott Haake, Anupama Reddy. Spatial biomarker prediction in papillary renal cell carcinoma using artificial intelligence-based immunofluorescent inference [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 3799.
Abstract 384: SLC7A11 modulates sensitivity to the first-in-class mitochondrial peroxiredoxin 3 inhibitor thiostrepton (RSO-021) via a ferroptosis independent pathway
Authors: Messier Terri , Gibson Victoria , Bzura Aleksandra , Dzialo Joanna , Poile Charlotte , Stead Stephanie , Saaman Alexis , Naumov George N. , Fennell Dean A. , Cunniff Brian 
Published: March 2024

Abstract
Mitochondrial peroxiredoxin 3 (PRX3) has been identified as an actionable cancer vulnerability that is currently being investigated in the first-in-human phase 1 clinical trial, MITOPE (NCT05278975). RSO-021 (thiostrepton or TS) is a redox-active drug that inhibits PRX3’s peroxidase activity via covalent adduction of its active site peroxidatic and resolving cysteine residues, forming an irreversible crosslink across the protein dimer. Covalent inhibition of PRX3 results in tumor cell death due to a diminished ability to remove high levels of mitochondrial reactive oxygen species (ROS) in cancer cells. To better understand the mechanism underpinning sensitivity and resistance, TS-tolerant human mesothelioma cell lines were generated under constant TS pressure and subjected to a drug-screen comprising chemotherapeutic agents, metabolic inhibitors, ROS modulating agents and ferroptosis-inducing compounds, to identify synergistic interactions compared with TS- sensitive cell lines. Erastin, an SLC7A11 inhibitor exhibited the greatest synergy when combined with TS, potentiated PRX3 covalent crosslinking and cellular ROS levels. Synergy with TS was enhanced by cystine depletion and could be phenocopied by siRNA knockdown of SLC7A11. SLC7A11 was up-regulated in TS-tolerant cells and resistance could be overcome with erastin. TS-tolerant cell lines have significantly reduced glutathione levels and slowed proliferation. Ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 did not inhibit TS or TS in combination with erastin. In summary, SLC7A11 up-regulation confers tolerance to TS through a mechanism involving a cysteine-dependent modulation of the redox state independent of canonical ferroptosis, that can be overcome by the addition of an SLC7A11 inhibitor. The correlation between SLC7A11 with response to TS in a 33-patient primary mesothelioma explant co-clinical trial, and patients enrolled into the MITOPE phase 1/2 trial will be presented.
Citation Format: Terri Messier, Victoria Gibson, Aleksandra Bzura, Joanna Dzialo, Charlotte Poile, Stephanie Stead, Alexis Saaman, George N. Naumov, Dean A. Fennell, Brian Cunniff. SLC7A11 modulates sensitivity to the first-in-class mitochondrial peroxiredoxin 3 inhibitor thiostrepton (RSO-021) via a ferroptosis independent pathway [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 384.
Abstract 3845: High-intensity focused ultrasound ablation increases tumor specific lymphocytes in prostate cancer
Authors: Su Shengchen , Wang Yanping , Lo Eric M. , Kim Hyung L. 
Published: March 2024

Abstract
The treatment of localized prostate cancer has been revolutionized by High-Intensity Focused Ultrasound (HIFU), an FDA-approved procedure. Thermal HIFU achieves the destruction of tumor tissue through the noninvasive delivery of ultrasonic energy, causing rapid heating of the targeted area. Given that prostate cancer typically exhibits a low presence of tumor-infiltrating lymphocytes crucial for antitumor immunity, this study aimed to investigate whether HIFU has the potential to activate antitumor immunity and enhance lymphocyte infiltration within the tumor. RM1 tumors were implanted on the flanks of syngeneic C57BL/6J mice, with one tumor subjected to HIFU treatment. The growth of the contralateral tumor was monitored, and at the end of the study, tumors were collected to evaluate immune cell infiltration. Blood samples were obtained from patients both before and after prostatectomy or HIFU treatment. Peripheral blood mononuclear cells (PBMCs) were then isolated to analyze the immune cell population. In murine experiments, the application of HIFU to one tumor resulted in a reduction in the growth of the contralateral (untreated) tumor, specifically when the contralateral tumor was of the same type, but not when it was a different tumor type. Notably, HIFU led to an augmented infiltration of CD4+ and CD8+ lymphocytes into the contralateral (untreated) tumor. Depletion studies further affirmed that the antitumor immune response triggered by HIFU relies on CD4+ and CD8+ lymphocytes. In human subjects, HIFU was observed to elevate the CD4+ and CD8+ lymphocyte populations in PBMCs. HIFU induces a potent antitumor immune response that effectively inhibits the progression of murine prostate tumors. This immune response is contingent upon CD4+ and CD8+ lymphocytes. HIFU demonstrates significant promise in activating antitumor immune responses in patients diagnosed with prostate cancer. Subsequent research endeavors should delve into models of metastatic prostate cancer, exploring the potential synergy of cytoreductive prostate tumor ablation with systemic immunotherapies to elicit a robust and comprehensive antitumor immune response.
Citation Format: Shengchen Su, Yanping Wang, Eric M. Lo, Hyung L. Kim. High-intensity focused ultrasound ablation increases tumor specific lymphocytes in 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 3845.
Abstract 3919: Targeting tissue-resident macrophage progenitors by anti-IL34 restores anti-tumor immunity and suppresses tumor growth
Authors: Chen Hui , Zak Jaroslav , Paradise Mark , Wang Guangfang , Teijaro John , Onaitis Mark , Varner Judith 
Published: March 2024

Abstract
Macrophages play important roles in tumor microenvironment, where they can promote immune suppression, tumor growth and resistance to checkpoint inhibitor therapy and are the focus of efforts to develop novel cancer therapeutics. Strategies to inhibit macrophage accumulation to suppress tumor growth by blocking their recruitment from circulation have been only partially effective, leading to the identification of roles in tumor progression for tissue resident macrophages that are seeded during embryonic development. We examined the origins of lung tumor associated macrophages using lineage tracing, flow cytometry, and single cell sequencing. By comparing gene expression profiles of resident F4/80hi Lyve1+ Ly6C- macrophages and Ly6C+ F4/80lo CCR2+ recruited macrophages in subcutaneous, lung, central nervous and renal normal and tumor tissues, we identified generic tissue resident macrophage and recruited macrophage transcriptomic signatures, revealing that resident macrophages are characterized by signatures of Myc driven proliferation, fatty acid and cholesterol metabolism and immune suppression, while recruited macrophages are characterized by signature of inflammation and immune stimulation. Resident macrophages were associated with worse outcomes in cancer patients than recruited macrophages. Single cell sequencing and flow cytometry of genetically engineered mouse models of CC10-Cre KrasG12D;p53-/- and SPC-Cre KrasG12D lung cancer revealed that lung tumor progression was characterized by extensive expansion of immune suppressive, Ki67+ resident alveolar macrophages and loss of T cells in the lung. Single cell transcriptomics identified IL-34 expressed exclusively by tumor cells as a possible driver of alveolar macrophage proliferation and IGF1 expressed by tumor associated alveolar macrophages as a possible regulator of tumor cell proliferation. Accordingly, blockade of IL-34 profoundly reduced tissue resident macrophage proliferation, stimulated recruitment of activated T cells, and suppressed growth of KrasG12D driven tumors. Analysis of TCGA data sets revealed that expression of IGF1 or IL34 was associated with reduced survival in lung, kidney, liver, head and neck and ovarian cancer. These studies identify key roles for IL-34 and IGF1 in solid tumor progression and suggest new therapeutic targets for the development of therapeutic strategies to stimulate anti-cancer immunity.
Citation Format: Hui Chen, Jaroslav Zak, Mark Paradise, Guangfang Wang, John Teijaro, Mark Onaitis, Judith Varner. Targeting tissue-resident macrophage progenitors by anti-IL34 restores anti-tumor immunity and suppresses tumor growth [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 3919.
Abstract 3970: Impairment of tumor reactive CD8 T cells in liver cancer
Authors: Trehan Rajiv S. , Soliman Marlaine , Wang Xin , Huang Patrick , Kedei Noemi , Zhu Xiao Bin , Seifert Matthias , Benmebarek Mohamed-Reda , Nur Amran , Korangy Firouzeh , Ma Chi , Greten Tim F. 
Published: March 2024

Abstract
Tumor reactive (TR) CD8 T cells in the liver have been studied in the setting of both immunotherapy and cellular therapy with the predominant dogma that these cells have equivalent functionality in the liver as compared to other organ sites. Herein, we detail that TR+ CD8 T cells are functionally impaired in the liver immune microenvironment in mice with liver tumors.TR+ CD8 T cells were studied in BALB/c and C57BL/6 mice injected intrahepatic, intravenous, and subcutaneously with either a colon (CT26) or a melanoma (B16F10) cancer cell line to create intrahepatic, pulmonary and subcutaneous tumors, respectively. Additionally, an ⍺CD8 antibody with IgG control was used to conduct functional studies. Samples were analyzed using flow cytometry and liver weights were measured. A high frequency of TR+ CD8 T cells were found in the liver in mice with intrahepatic tumors. Despite ~70% of CD8 T cells being tumor reactive in intrahepatic tumors, liver tumor growth kinetics were faster than subcutaneous tumors. Higher proportion of the TR+ CD8 T cells were found to be exhausted in the liver tumor by flow cytometry. Functional depletion of the CD8 T cells caused a fivefold higher tumor growth in the subcutaneous model but in contrast had no effect on intrahepatic tumors. In conclusion, despite the high frequency of “killer” tumor reactive T cells in the liver, the growth kinetics of the liver tumors, flow cytometry as well as functional studies demonstrate the impairment of TR+ CD8 T cells in the liver. We aim to dissect the mechanisms mediating intrahepatic TR CD8+ T cell exhaustion in primary liver tumors as well as metastatic models. Additionally, we aim to determine significant costimulatory molecules specific to intrahepatic exhaustion which could lead to better therapeutic models.
Citation Format: Rajiv S. Trehan, Marlaine Soliman, Xin Wang, Patrick Huang, Noemi Kedei, Xiao Bin Zhu, Matthias Seifert, Mohamed-Reda Benmebarek, Amran Nur, Firouzeh Korangy, Chi Ma, Tim F. Greten. Impairment of tumor reactive CD8 T cells in liver 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 3970.
Abstract 3984: Full-length TCR and BCR repertoire analysis, integrated with mRNA and surface proteins characterization, in a tumor mouse model
Authors: Rezvan Ali , Shi Xiaoshan , Sen Moen , Widmann Stephanie , Tyznik Aaron 
Published: March 2024

Abstract
Full-length TCR and BCR analysis with single-cell multiomic assays provides an understanding of immune responses, offering insights into the complete receptor structure and functionality that is crucial for accurately assessing the diversity and specificity of immune repertoires. Studying mouse immune cell heterogeneity can be achieved by simultaneous mRNA and surface protein profiling. However, when coupled with full-length TCR and BCR analysis, this integrated approach provides a more comprehensive understanding of immune responses and cellular function in healthy and diseased conditions. In this study, we used the MC38 colon carcinoma model to study T and B cell heterogeneity and clonotype diversity. We stained single-cell suspensions prepared from bone marrow, thymus, spleen and tumor tissues with 20 AbSeq (CITE-Seq) antibody oligos and sample-multiplexing tags. We then loaded 50,000 isolated T and B cells into two lanes of an 8-lane microwell cartridge for single-cell capture by a single-cell analysis system. To aid in the simultaneous analysis of clonality and gene expression, we carried out library preparation using a full-length TCR/BCR multiomic assay and a mouse immune response panel. The combination of mRNA and protein expression confirmed the elevated expression of exhaustion and activation markers in tumor-infiltrating lymphocytes (TILs). We identified high-frequency clonotypes within TILs and tracked their frequency across other tissues. Tumor-burdened mice splenic T cells showed shared TCR combinations with TILs, which were absent in healthy tissue. The results show the ability to successfully profile T and B cell receptors using a full-length TCR/BCR multiomic assay in a mouse tumor model and the use of transcriptome, protein and TCR/BCR clonal information to investigate immune cell characteristics across multiple samples.
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Citation Format: Ali Rezvan, Xiaoshan Shi, Moen Sen, Stephanie Widmann, Aaron Tyznik. Full-length TCR and BCR repertoire analysis, integrated with mRNA and surface proteins characterization, in a tumor mouse 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 3984.
Abstract 3986: Exploring nonsense-mediated decay inhibition as a novel approach to improve immunogenicity in small cell lung cancer
Authors: Fernández Lucia A. Torres , Böhm Volker , Maas Lukas , Schöllhorn Anna , Kaufmann Joel , D'Rozario Joshua , Kaiser Laura , Gehring Niels , Peifer Martin , Gouttefangeas Cécile , Thomas Roman K. , George Julie 
Published: March 2024

Abstract
Cancer immunotherapy has revolutionized the field of oncology and is one of the most promising treatments for lung cancer. Small cell lung cancer (SCLC) is highly aggressive and patients often relapse due to chemotherapy resistance. In the recent years, chemotherapy has been combined with immune checkpoint inhibition (ICI) for SCLC treatment, leading to improved responses in some patients, but also leaving a high number of non-responders to address. Paradoxically, SCLC has one of the highest tumor mutational burden, including remarkably abundant frameshifts (FS) which could create highly immunogenic neoantigens (NeoAg). However, FS-harbouring transcripts are often degraded via Nonsense-Mediated Decay (NMD). We therefore aimed to inhibit the NMD pathway to increase the immunogenicity of SCLC.
Our lab has so far profiled the mutational landscape of more than 400 SCLC patients and generated over 100 patient-derived xenotransplant models. We analyzed genome and transcriptome sequencing data of multiple tumors to interrogate the NMD target repertoire in SCLC. We determined tumor-specific mutations and predicted NeoAg based on the HLA-I-binding ability of mutant peptides. Upon NMD inhibiton, we validated the expression and presentation of NeoAg via transcriptomics, proteomics and HLA-I-immunopeptidomics. NMD-sensitive mutated transcripts included a wide range of somatic alterations beyond FS-mutations, suggesting an overall increase of potential tumor-specific NeoAg. We furthermore evaluated immunogenicity after NMD perturbation employing in vitro co-cultures as well as immunocompetent in vivo mouse models. Inhibition of NMD in tumor cells resulted in an HLA-I-dependent enhancement of T cell-mediated tumor killing in vitro, and in vivo experiments showed reduced tumor growth accompanied by increased immune infiltration upon controlled induction of NMD inhibition.
Altogether, NMD inhibition in SCLC led to an upregulation of NeoAg expression in tumor cells accompanied by enhanced T cell responses in vitro and in vivo. Our strategy provides a novel approach for the treatment of low immunogenic tumors which could be combined with ICI to enhance the efficacy of immunotherapy.
Citation Format: Lucia A. Torres Fernández, Volker Böhm, Lukas Maas, Anna Schöllhorn, Joel Kaufmann, Joshua D'Rozario, Laura Kaiser, Niels Gehring, Martin Peifer, Cécile Gouttefangeas, Roman K. Thomas, Julie George. Exploring nonsense-mediated decay inhibition as a novel approach to improve immunogenicity in 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 3986.