bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6556: Targeting mesenchymal tumor cell-intrinsic factors sensitizes refractory tumors to immune checkpoint blockade therapy
Authors: Bakhle Kimaya M. , Sams Caitie H. , Dongre Anushka 
Published: March 2024

Abstract
Immune checkpoint blockade (ICB) therapy has emerged as a promising approach for treating breast cancer, however, only a fraction of patients derives clinical benefit and the underlying reasons for heterogeneous responses remain elusive. The epithelial-to-mesenchymal transition (EMT) enables these carcinomas to metastasize and acquire resistance to chemotherapy. We have recently demonstrated that the EMT program also confers resistance to immunotherapies. Specifically, epithelial tumors recruit CD8+ T-cells to the tumor microenvironment and are sensitive to anti-CTLA4 ICB. In contrast, mesenchymal tumors assemble an immunosuppressive tumor microenvironment and are resistant to the same treatment. Furthermore, mesenchymal tumors express multiple immunosuppressive paracrine factors relative to their epithelial counterparts. Of these, abrogation of CSF1 or SPP1 from mesenchymal cancer cells generates partial responses to ICB therapy. Strikingly, abrogation of CD73 from mesenchymal carcinoma cells completely sensitizes otherwise refractory tumors to immunotherapy. While targeting cancer cell-intrinsic factors can sensitize mesenchymal tumors to ICB, the mechanisms that dictate partial versus complete responses are unclear. Furthermore, whether abrogation of CD73 can also sensitize mesenchymal tumors to other forms of ICB remains unknown. By performing immunofluorescent analysis of tumor sections, we observed that knockout of CD73 promoted the greatest infiltration of both CD4+ and CD8+ T-cells in response to anti-CTLA4 ICB compared to tumors knocked out for CSF1 and SPP1, which showed only intermediate levels of infiltration. Moreover, treatment of mesenchymal tumor-bearing mice with anti-CD73 generated synergistic responses with anti-CTLA4 ICB, but not with anti-PD1, or combinations of anti-CTLA4 and anti-PD1. In conclusion, our results demonstrate that the EMT program in cancer cells is predictive of responses to ICB. Targeting CD73 in mesenchymal breast tumors promotes an influx of both CD4+ and CD8+ T-cells and potentiates the efficacy of anti-CTLA4 ICB. Through mining of canine mammary tumor RNA sequencing data, we have found that canine tumors associated with EMT have increased expression of CD73, which suggests that these mechanisms of immune evasion may translate across species. These findings could promote therapies for both animals and humans that sensitize highly refractory populations of more-mesenchymal cancer cells.
Citation Format: Kimaya M. Bakhle, Caitie H. Sams, Anushka Dongre. Targeting mesenchymal tumor cell-intrinsic factors sensitizes refractory tumors to immune checkpoint blockade therapy [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 6556.
Abstract 6624: MYC promotes lobuloalveologenesis and mammary tumorigenesis in male mice
Authors: Pulver Emilia M. , van der Burg Eline , Drenth Anne Paulien , Yemelyanenko Julia , Ravensbergen Nils , de Bruijn Roebi , Klarenbeek Sjoerd , Song Ji-Ying , Boeije Manon , Siteur Bjørn , Proost Natalie , Scheele Colinda , Bouwman Peter , Jonkers Jos 
Published: March 2024

Abstract
Male breast cancer is a rare disease that is largely overlooked and clinically regarded to recapitulate female breast cancer biology. The worse overall outcome for male patients compared to females, however, underscores inadequate disease management and a sex-based divergence in disease biology. To gain more insight into male breast biology and pathology, we used mouse models of triple-negative breast cancer and 3D whole-mount confocal imaging techniques to evaluate both in vivo and ex vivo mammary gland development, tumor formation, and hormone signaling dependence. Our results show that Myc overexpression in collaboration with Trp53 deficiency drives mammary tumorigenesis in male mice. We show that MYC overexpression promotes estrogen-independent formation of lobuloalveolar structures, which progress into tumors with a similar histology and immune landscape as female mammary tumors but with significantly more genomic instability. In female mice, MYC overexpression bypasses the dependency on paracrine estrogen signaling in mammary tumorigenesis. These data provide robust evidence that MYC overrides mammary tumor estrogen dependence and abolishes the tumor-preventive effect of a low-estrogen environment. Supporting this notion, in vitro experiments in human female breast cancer cell lines indicate that MYC overexpression may functionally contribute to endocrine therapy resistance and therefore could possibly serve as a prognostic biomarker or clinically targetable pathway for treating both male and female breast cancers. Collectively, this preclinical work presents new insights into male mammary gland biology and mechanisms of cancer progression that might translate to a broader range of breast cancers in the clinic.
Citation Format: Emilia M. Pulver, Eline van der Burg, Anne Paulien Drenth, Julia Yemelyanenko, Nils Ravensbergen, Roebi de Bruijn, Sjoerd Klarenbeek, Ji-Ying Song, Manon Boeije, Bjørn Siteur, Natalie Proost, Colinda Scheele, Peter Bouwman, Jos Jonkers. MYC promotes lobuloalveologenesis and mammary tumorigenesis in male mice [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 6624.
Abstract 6633: Tracking cell-cell interactions using intercellular barcode transfer
Authors: Tay Neil Q. , Juan Tiffany , Muldoon Joseph J. , Eyquem Justin , McManus Michael T. 
Published: March 2024

Abstract
Cell-cell interaction is one of the fundamental biological mechanisms by which cells communicate and is a key modality by which cancer cells interact with other cells in their microenvironment. Current methods, such as enzymatic labeling and proximity-based tagging, allow the experimental tracking of these interactions but are not compatible with sequencing-based readouts, which are essential for high-throughput analyses. We have developed a highly scalable intercellular barcode transfer technology that bridges this gap. Our novel “Relay” technology offers a scalable solution to monitor cell-cell interactions with unprecedented single-cell resolution, seamlessly integrating with existing high-throughput and sequencing platforms. Relay employs RNA barcodes to mark and track cell interaction events, providing definitive quantitative data on cell interaction partners. We used Relay to track interactions between cancer cells and T cells, capturing both potent antigen-specific engagements and subtler contacts involved in antigen sampling. Additionally, by integrating CRISPR libraries with Relay, we pioneered a novel approach for pooled CRISPR screens, focusing on intercellular interactions across different cell types. In this context, the cell harboring genetic perturbation may differ from the cell under analysis. To demonstrate this, we are conducting genome-wide perturbations in cancer cells and interrogating cancer cell factors that affect antigen sampling and trogocytosis by T cells and macrophages. Beyond its application in CRISPR screening, Relay can also be used with single-cell RNA sequencing to directly track and measure immune-cancer and immune-immune cell interactions at the single cell level. We applied single-cell Relay to a dendritic cell-T cell system to link dendritic cell signatures to T cell signatures based on direct cell contact and regulatory signaling. The design of Relay as a highly modular system extends its utility beyond cancer research, making it broadly applicable across various biological models and systems where cell-cell communication is a fundamental property in complex multicellular settings. This tool promises to accelerate the transition from theoretical understanding to practical exploration of cell-cell interactions, with profound implications for immunology, oncology, and beyond.
Citation Format: Neil Q. Tay, Tiffany Juan, Joseph J. Muldoon, Justin Eyquem, Michael T. McManus. Tracking cell-cell interactions using intercellular barcode transfer [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 6633.
Abstract 6664: In situ vaccination with hyper-interferon sensitive influenza induces adaptive immune response and sensitizes murine non-small cell lung cancer to PD-1 blockade
Authors: Salehi-Rad Ramin , Du Yushen , Zhang Tianhao , Shi Yuan , Liu Bin , Ren Sun 
Published: March 2024

Abstract
Despite recent advances in immunotherapy with immune checkpoint inhibitors (ICI), many patients with non-small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. The exclusion of T cells from the tumor or the presence of a dysfunctional T cell compartment within the tumor microenvironment (TME) constitute two central hallmarks of resistance to ICI in patients with NSCLC. Seminal studies have identified that loss of LKB1 in KRAS-mutant NSCLC drives resistance to ICI, potentially by suppressing STING, thereby leading to dysregulation of the interferon (IFN) signaling. There is a pressing demand for the development of innovative immune therapies designed to bolster anti-tumor T cell responses to overcome resistance to ICI. In situ vaccination (ISV) with oncolytic viruses has emerged as a promising, antigen-agnostic strategy capable of conditioning the TME and amplifying anti-tumor T cell responses. We engineered a live attenuated viral vaccine, Hyper-Interferon Sensitive virus (HIS), by conducting a genome-wide functional screening and introducing eight interferon (IFN)-sensitive mutations in the influenza A genome. We utilized multiple syngeneic murine models of NSCLC with distinct driver mutations [KrasG12D/P53+/−/Lkb1−/− (KPL); KrasG12D/P53+/− (KP); and KrasG12D (K)] and varying tumor mutational burden to assess the safety and efficacy of intratumoral HIS virotherapy. Compared to wild-type (WT) influenza, HIS replication was attenuated, enhancing its potential as a safe option for cancer therapy. HIS ISV elicited robust yet transient type I IFN responses in murine NSCLCs, leading an influx of polyfunctional effector Th1 CD4 and cytotoxic CD8 T cells into the tumor. HIS ISV demonstrated enhanced anti-tumor efficacy compared to WT in multiple syngeneic murine models of NSCLC. This efficacy was dependent on host type 1 IFN responses and T lymphocytes. HIS ISV synergized with anti-PD-1 to eradicate immune resistant LKB-1 deficient NSCLC in a subset of mice, resulting in improved overall survival and enduring systemic tumor-specific immunity. These studies provide compelling evidence to support further clinical evaluation of HIS as a novel ‘off-the-shelf’ ISV strategy for patients with NSCLC refractory to ICI.
Citation Format: Ramin Salehi-Rad, Yushen Du, Tianhao Zhang, Yuan Shi, Bin Liu, Sun Ren. In situ vaccination with hyper-interferon sensitive influenza induces adaptive immune response and sensitizes murine non-small cell lung cancer to PD-1 blockade [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 6664.
Abstract 6670: Could immunotherapy offer potential in managing bacterial dysbiosis in prostate cancer
Authors: Oliver Tim , Nedjai Belinda , Lane Emily , Chinegwundoh Frank , Rajan Prabhakar , Cuzick Jack 
Published: March 2024

Abstract
Background: Since 2006 three studies, involving 289,089 adolescents, demonstrated a significant association (1.67(0.79-3.55),1.7(1.03-2.70),2.37(1.19-4.73)) between pubertal acne and poor outcome prostate cancer(PC) 30+ years later. This suggested Cutibacterium acnes, amicroaerophylic bacterium, might be contributing to PC bacterial dysbiosis analogous to the role of H. pylori in stomach cancer and explain why circumcision reduces PC risk. Six years ago, using MALDI-TOF, we demonstrated that the presence of seven obligate anaerobe species in addition to C. acnes were increased in PC and linked to increased PSA. This presentation studies stored samples from the PROVENT chemoprevention randomised PC active surveillance phase 2 trial analysed using 16S rDNA sequencing, and comparing obligate anaerobe frequency with those detected by culture and MALDI-TOF identification and their influence on PSA expression.
Methods: 89 urines of PROVENT trial patients were studied using 16S rDNA sequencing and followed for 24 months. In addition, 39 previously reported MALDI-TOF screened cohort patients (21 PCs and 18 BPHs) followed for 43 months. The frequency of 7 obligate bacterial genera (Actinobaculum, Finegoldia, Prevotella, Peptoniphilus, Peptostreptococcus & Viellonella) was studied.
Results: Twenty six of 89 (29%) PROVENT urine samples had a majority of bacteria detected as obligate anaerobes (mean=68%), while it was 12 of the 39 (31%) in PC tested in MALDI-TOF. In the combined series, those patients (n=38) with obligate anaerobes had mean PSA of 9.59 ug/L, while those without obligate anaerobes had a mean PSA of 6.29 ug/L (n=90), (t=-2.925, p = 0.0058). In the MALDI-TOF series, statistically increased urological intervention rate was associated with the presence of anaerobes (p=0.045, Fisher’s exact test).
Discussion: These findings suggest that obligate anaerobe bacterial dysbiosis could be contributing to raised PSA through prostate cell damage, and possibly participating in the chronic inflammation and hypervascular changes that are seen in precancerous lesions. Checkpoint inhibitors have shown little benefit in prostate cancer. Recent reports from animal model studies of BCG resistance have suggested a short course combination of anti PDLI and anti NKG2a could break immune tolerance associated with expression of HLA-E and this approach could be of use to break tolerance to bacterial dysbiosis in the future.
Citation Format: Tim Oliver, Belinda Nedjai, Emily Lane, Frank Chinegwundoh, Prabhakar Rajan, Jack Cuzick. Could immunotherapy offer potential in managing bacterial dysbiosis 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 6670.
Abstract 6672: Unraveling the microbiome: antibiotic impact on CAR T therapy and the synergistic potential of vancomycin in enhancing antitumor immunity
Authors: Facciabene Andrea , Uribe-Herranz Mireia , Bhoj Vijay 
Published: March 2024

Abstract
The landscape of treating hematologic malignancies has undergone a revolutionary transformation with the advent of Anti-CD19 chimeric antigen receptor T cell therapy (CART-19). Despite its success, persistent challenges like disease relapse and CAR-mediated toxicities remain. A comprehensive multicenter study involving 228 individuals revealed a significant association between antibiotic administration, particularly piperacillin/tazobactam, meropenem, and imipenem/cilastatin (P-I-M), targeting anaerobes within four weeks preceding CART-19 therapy, and adverse outcomes, including worsened survival and increased neurotoxicity. Intriguingly, another antibiotic, Cefepime, also used for neutropenic fever, displayed a positive trend when compared with P-I-M. This highlights the intricate relationship between the modulation of the intestinal microbiome and outcomes in CART-19 therapy for B cell malignancies. Building on these critical observations, our study delved into the impact of vancomycin-induced gut microbiota dysbiosis on chimeric antigen receptor (CAR) T immunotherapy. Utilizing preclinical models of CD19+ A20 lymphoma and CD19+ B16 melanoma, we discovered that mice receiving vancomycin alongside CART-19 therapy exhibited enhanced tumor control and increased cross-presentation of tumor-associated antigens (TAAs) compared to those receiving CART-19 alone. This effect was further validated through fecal microbiota transplants from healthy human donors to pre-conditioned mice, replicating the favorable findings. Importantly, our study extends to clinical correlates, as B cell acute lymphoblastic leukemia patients treated with CART-19 and oral vancomycin displayed elevated CART-19 peak expansion compared to unexposed patients. These compelling results underscore the profound influence of the gut microbiota on CAR T cell therapy and suggest that vancomycin-induced gut microbiota modulation may emerge as a potent strategy to enhance therapeutic outcomes across various tumor types.
Citation Format: Andrea Facciabene, Mireia Uribe-Herranz, Vijay Bhoj. Unraveling the microbiome: antibiotic impact on CAR T therapy and the synergistic potential of vancomycin in enhancing antitumor immunity [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 6672.
Abstract 6714: AI-guided tailor-made anti-TROP2 T-cell engagers for T-cell mediated cancer immunotherapy with enhanced therapeutic index
Authors: Chen Chuan , Tian Liang , Su Chenpeng , Liu Dandan , Chen Xiaoqian , Zhou Yifei , Jiang Suze , Wang Guifang , Tian Jiyuan , Yuan Yuan , Yang Bing , Peng Jian 
Published: March 2024

Abstract
Bispecific T-cell engagers (TCEs) have shown significant therapeutic advances in the treatment of hematologic cancers. However, the clinical efficacy of TCEs in treating solid tumors remains to be demonstrated. Accumulating evidence suggests novel TCE modalities that simultaneously engage both CD3 (signal 1) and CD28 (signal 2) co-stimulatory signals may offer potential advantage to enhance clinical efficacy of TCEs with improved therapeutic index. To explore the full potential of TCEs as a powerful approach of immunotherapy for solid tumors, we developed an integrated AI-guided TCE platform to streamline the discovery, optimization and high-throughput function screening and characterization of TCE molecules. Here we report the construction and characterization of a novel panel of TROP2-targeting TCEs by leveraging our AI-guided optimization technology, plus a high-throughput in vitro screening platform. These tailor-made TCE molecules exhibit favorable developability and functional properties. Our data show that a novel TROP2 × CD3 x CD28 trispecific TCE that contains a CD3-targeting arm in concomitant with a CD28-targeting arm can induce potent T-cell co-stimulation and promising synergistic T cell-mediated tumor cell killing in vitro, compared to its counterparts with a single CD3-targeting arm. We further generate a trivalent TROP2 x CD3 bispecific TCE constructed as an asymmetric ‘2+1’ format with bivalent binding to TROP2 but a monovalent CD3-targeting arm. This molecule stimulates very low levels of cytokine release, but drives robust antigen-specific killing in in vitro assessment. Anti-tumor activity of the various TROP2 x CD3 TCEs is currently being investigated in multiple tumor xenograft mouse models.
Citation Format: Chuan Chen, Liang Tian, Chenpeng Su, Dandan Liu, Xiaoqian Chen, Yifei Zhou, Suze Jiang, Guifang Wang, Jiyuan Tian, Yuan Yuan, Bing Yang, Jian Peng. AI-guided tailor-made anti-TROP2 T-cell engagers for T-cell mediated cancer immunotherapy with enhanced therapeutic index [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 6714.
Abstract 6752: Targeting of neoantigen cancer vaccines to antigen presenting cells results in faster and broader T cell responses whether encoded in DNA or mRNA
Authors: Weinert Brian T. , Skullerud Lise , Solbakken Eirik , Textor Ana , Dürkoop Mirjam , Winge Inga Patrycja , Norheim Gunnstein , Stubsrud Elisabeth , Granum Stine , Pedersen Mikkel W. , Norell Håkan 
Published: March 2024

Abstract
Individualized cancer vaccines based on patient-specific neoantigens represent a groundbreaking approach in oncology, offering a highly individualized treatment option for cancer patients. Unlike traditional vaccines, which are designed to prevent diseases by stimulating an immune response against a specific pathogen, personalized cancer vaccines are therapeutic, aiming to treat cancer by training the immune system to recognize and attack the patient’s own cancer cells. The key is to induce a fast, strong, broad, and persistent CD8+ T cell response.
Nykode Therapeutics has developed a platform that targets antigens directly to antigen presenting cells (APCs) using a modular dimeric protein format known as a VaccibodyTM. Individualized neoantigen vaccines delivered in a DNA-encoded Vaccibody format have been shown to induce strong and broad T cell responses in pre-clinical and clinical settings.
Here, we wanted to determine if the APC-targeted approach leads to superior T cell responses if Vaccibody vaccines are encoded in mRNA and administered in a lipid nanoparticle (LNP) formulation. For this purpose, we designed and evaluated a model cancer vaccine composed of 20 unstructured 27 amino acid long neoantigens derived from the murine MC38 tumor model.
A DNA-encoded Vaccibody vaccine elicited faster T cell responses compared to an untargeted mRNA-LNP-encoded vaccine. DNA-encoded Vaccibody responses were also broader, targeting a substantially greater number of neoantigens.
Next, we compared the APC-targeting Vaccibody vaccine to an untargeted vaccine when both were formulated in an mRNA-LNP format. The APC-targeting Vaccibody vaccine elicited a greater breath and magnitude of T cell responses compared to the untargeted vaccine. Further studies to evaluate the functional differences associated with the various formats, in terms of T cell phenotype and response to tumor challenge, are ongoing.
In summary, the data demonstrate that an APC-targeted Vaccibody vaccine containing MC38 neoantigens can be encoded in both DNA and mRNA-LNP to induce faster, broader, and stronger T cell responses compared to a non-targeted neoantigen vaccine.
Citation Format: Brian T. Weinert, Lise Skullerud, Eirik Solbakken, Ana Textor, Mirjam Dürkoop, Inga Patrycja Winge, Gunnstein Norheim, Elisabeth Stubsrud, Stine Granum, Mikkel W. Pedersen, Håkan Norell. Targeting of neoantigen cancer vaccines to antigen presenting cells results in faster and broader T cell responses whether encoded in DNA or mRNA [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 6752.