bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B035: Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer
Authors: DeMarco Kelly D , Chibaya Loretah , Lusi Christina F , Kane Griffin I , Brassil Meghan L , Parikh Chaitanya N , Murphy Katherine C , Chowdury Shreya R , Li Junhui , Ma Boyang , Taylor Tiana E , Cerrutti Julia , Mori Haruka , Diaz-Infante Miranda , Peura Jessica , Pitarresi Jason R , Zhu Lihua Julie , Fitzgerald Katherine A , Atukorale Prabhani U , Ruscetti Marcus 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer- related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-mediated tumor regressions and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated Type I interferon-driven innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC.
Citation Format: Kelly D DeMarco, Loretah Chibaya, Christina F Lusi, Griffin I Kane, Meghan L Brassil, Chaitanya N Parikh, Katherine C Murphy, Shreya R Chowdury, Junhui Li, Boyang Ma, Tiana E Taylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R Pitarresi, Lihua Julie Zhu, Katherine A Fitzgerald, Prabhani U Atukorale, Marcus Ruscetti. Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B035.
Abstract B037: Banana Lectin expressing CAR T cells to target Pancreatic Cancer
Authors: McKenna Katie , Ozcan Ada I , Markovitz David , Brenner Malcolm K 
Published: September 2024

Abstract
To overcome both the heterogenous and dynamic expression of tumor antigen expression in pancreatic ductal adenocarcinoma (PDAC) and the physical barrier provided by the associated fibrotic stroma, we have developed a novel therapy that recognizes and binds to distinct patterns of aberrant glycosylation specifically expressed on tumor cells and their surrounding stroma. Aberrant glycosylation patterns are a hallmark of cancer and are widely present on tumors including PDAC. We therefore incorporated H84T BanLec as part of a chimeric antigen receptor and co-expressed the construct in T cells and showed that H84T BanLec CAR expressing T-cells can effectively target pancreatic tumors. We hypothesized that our novel lectin CAR would enhance the activity of T cells when co-expressed with conventional scFV – derived CARs targeting tumor associated antigens We compared the activity of dual-expressing H84T/HER.2 CAR-T or H84T/PSMA CAR-T cells against single- expressing CARs targeting PDAC. We determined anti-tumor cytotoxicity by measuring residual GFP+ tumor cells in a sequential killing assay using flow cytometry. We observed superior anti-tumor activity using dual expressing CAR T cells compared to T cells expressing either HER.2- or H84T- or PSMA- CAR alone. Similarly, in 3D multicellular spheroids containing tumor and cancer-supportive stromal cells, an IncuCyte live imaging assay shows dual CAR T cells have greater cytotoxicity against PDAC than single CAR expressing T cells (p= 0.02 H84T/HER.2 vs HER.2 CAR; p=0.00003 H84T/PSMA CAR vs PSMA CAR). These results also translate to improved anti- tumor function of dual CAR T cells in PDAC xenograft in vivo models where H84T/HER.2 CAR T cells significantly reduced the tumor volume burden (p=0.015; H84T/HER.2 average=57.1mm3; HER.2 average=116.1mm3; H84T average=130.3mm3). These findings suggest that H84T BanLec CAR T cells provide a tool to target the aberrant glycosylation patterns of malignant cells and their supporting stroma and may contribute to an effective treatment option for PDAC patients. We are now elucidating the underlying mechanism by which H84T BanLec CARs enhance tumor activity and promote T cell infiltration.
Citation Format: Katie McKenna, Ada I Ozcan, David Markovitz, Malcolm K Brenner. Banana Lectin expressing CAR T cells to target Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B037.
Abstract B038: Tumor Derived Parathyroid Hormone Related Protein is an Orchestrator of Immunosuppression in Pancreatic Cancer
Authors: Johnson Calvin , Pitarresi Jason 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has the lowest 5-year survival of common cancers, owing to a lack of early detection and ineffective therapies. Immune checkpoint inhibitors hold promise for PDAC patients, and while they represent the most ongoing clinical trials, they have had little success. Parathyroid Hormone Related Protein (PTHrP; encoded by PTHLH) defines the most aggressive squamous/basal/quasi-mesenchymal PDAC subtype. Our previous work revealed autocrine PTHrP signaling mediates tumor growth, epithelial-to-mesenchymal transition (EMT), and metastasis. However, PTHrP’s relationship with immune cells of the tumor microenvironment (TME) remains unknown. Investigation of tumors from KrasG12D; p53R172H; Pdx1-Cre; YFP (KPCY) and KPCY-Pthlh loxP/WT (KPCY-Pthlhhet) mice revealed less tumor associated neutrophils (TANs) and greater cytotoxic T cell infiltration, demonstrating the necessity of PTHrP for immune exclusion. Orthotopic implantation of Pthlh overexpressing KPCY cells (KPCY-PthlhOE) revealed a greater proportion of TANs than the control. A concomitant decrease in the number of effector T and natural killer cells in the KPCY-PthlhOE tumors was observed, showing PTHrP is sufficient to organize an immunosuppressive TME. Interestingly, recombinant human PTHrP was sufficient to induce TANs mobilization in vivo. To interrogate the mechanism of neutrophil trafficking into the TME, cytokine production was quantified in vitro. KPCY-PthlhOE exhibited a pronounced increase of Cxcl1 expression, a strong neutrophil chemokine, leading us to believe neutrophils migrate to the TME using a Cxcl1 gradient. Therefore, we hypothesized that PTHrP-mobilized neutrophils express the receptor for CXCL1; CXCR2. Indeed, recombinant PTHrP was sufficient to mobilize Cxcr2+ neutrophils in vivo. Furthermore, recombinant PTHrP was able to induce Cxcl1 production by KPCY tumor cells in vitro in a cAMP response element-binding protein(CREB)-dependent manner. These data describe a novel mechanism for the mobilization and infiltration of immune suppressive TANs into the TME, initiated by PTHrP. The PTHrP-dependent immunosuppressive TME excludes and inhibits effector immune cells. Further interrogation of PTHrP signaling during the genesis of the immune suppressive TME in PDAC may lead to the development of therapeutics to meet this unmet clinical need.
Citation Format: Calvin Johnson, Jason Pitarresi. Tumor Derived Parathyroid Hormone Related Protein is an Orchestrator of Immunosuppression in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B038.
Abstract B040: B cells facilitate lymph node colonization in pancreatic ductal adenocarcinoma
Authors: Bertocchi Alice , Hoffman Megan T , Qiang Li , Morell Massiel , Hsu Lauren L , Dougan Michael L , Agudo Judith , Dougan Stephanie K 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) carries a low survival rate. Several factors contribute to its dismal prognosis, including resistance to available therapies and high invasiveness. Lymph nodes act as an early systemic source of circulating malignant cells, allowing their dissemination to other organs early in disease progression. Lymphatic colonization is linked to worse prognosis, and a better understanding of mechanisms regulating lymph node metastasis is clinically needed. To study each step in the metastatic cascade to the lymph nodes, we have developed a mouse co-clinical model of resectable pancreatic cancer. This model mimics the frequency of human PDAC metastatic recurrence, on a similar time scale relative to the lifespans of mice and humans and allows us to investigate very early events in the metastatic cascade. In contrast to the established anti-tumor role of T cells, the role of B cells in cancer immunology is more complex. B cells are a predominant immune population in lymph nodes, but their role in relation to lymph node colonization has never been fully addressed. Using our model of PDAC spontaneous metastasis and a mouse model of B cell depletion, we showed that lymph node metastasis does not form in the absence of B cells. We demonstrated that B cells, but not secreted antibodies, are required for successful lymph node colonization. We also gained evidence that B cells are orchestrating a complex interplay between disseminated cancer cells and other immune cells in the draining lymph node. Particularly, T cells seem to be involved in preventing cancer cell from growing into macro-metastasis only in the absence of B cells. We are now investigating the mechanisms employed by B cells to facilitate this cellular network to facilitate lymph node colonization in PDAC. The ultimate outcome of our work will be the design of effective immune strategies to prevent and treat lymph node dissemination of such a deadly disease.
Citation Format: Alice Bertocchi, Megan T Hoffman, Li Qiang, Massiel Morell, Lauren L Hsu, Michael L Dougan, Judith Agudo, Stephanie K Dougan. B cells facilitate lymph node colonization in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B040.
Abstract B041: Fibroblast STAT3 Signaling in Pancreatic Cancer: Implications for Immunotherapy and Tumor Microenvironment Modulation
Authors: Saberi Samaneh , Bumbleburg Cameron , Everett Caroline , Lefler Julia E , Jordan Victoria , Han Lu , Sharma Sudarshana , Ostrowski Michael C. 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer distinguished by a dense stromal microenvironment. The current investigation delves into the fibroblast-specific STAT3 signaling in the PDAC tumor microenvironment (TME) and its effects on immune cell infiltration and extracellular matrix (ECM) modulation. An association was identified between heightened levels of phosphorylated STAT3 (pSTAT3) in tumor-associated fibroblasts (CAFs) and a more unfavorable prognosis, particularly among male patients. Comparative analysis of gene expression patterns in normal fibroblasts and those deficient in STAT3, extracted from mouse models of pancreatic cancer, unveiled distinct gene expression profiles related to the inflammatory signaling pathway (IL6, ADM, CXCL11, CD80, VEGFA, TGFB1, STC1, STC2). Utilizing ChIP-Seq analysis with an anti-pSTAT3 antibody, it was confirmed that STAT3 binds to the regulatory regions of these genes, supporting its regulatory role in the inflammatory signaling pathway. Moreover, the absence of STAT3 in CAFs resulted in a decline in M2 macrophages and an upsurge in M1 macrophages within the TME, indicating a potential function of STAT3 in influencing macrophage polarization. Noteworthy observations also revealed that STAT3 signaling in CAFs impacts ECM remodeling, as illustrated by reduced collagen deposition. Furthermore, the deficiency of STAT3 in CAFs led to a notable reduction in the quantity of neutrophils within the TME in our mouse model. Additionally, a plausible involvement of STAT3 in neutrophil recruitment and activation through the CXCL1/CXCR2 axis was indicated. Alterations in the infiltration of neutrophils and macrophages due to the absence of STAT3 could profoundly influence the immune response against PDAC. The modified composition of ECM following STAT3 deletion might also impact the infiltration and functioning of immune cells. These outcomes underscore the significance of STAT3 signaling in CAFs as a promising therapeutic target in PDAC, offering potential for modulating the tumor microenvironment, augmenting anti-tumor immunity, and advancing patient outcomes.
Citation Format: Samaneh Saberi, Cameron Bumbleburg, Caroline Everett, Julia E Lefler, Victoria Jordan, Lu Han, Sudarshana Sharma, Michael C. Ostrowski. Fibroblast STAT3 Signaling in Pancreatic Cancer: Implications for Immunotherapy and Tumor Microenvironment Modulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B041.
Abstract B047: Antigenic properties determine the outcome of B cell driven anti-tumor immunity
Authors: Sturdevant Colleen , Kren Nancy , Silva Harrison , Gomez Ismael , Hepperla Austin , Pylayeva-Gupta Yuliya 
Published: September 2024

Abstract
B cells have the capacity to elicit both anti- and pro-tumorigenic effects; yet the determinants of productive B cell responses in cancer remain elusive. Using a system where a B cell neoantigen is either soluble or tethered to the surface of pancreatic cancer cells, we demonstrate that membrane-tethered antigen is sufficient to elicit activation of anti-tumor immunity and reduce tumor growth in an NK cell-dependent manner. We also show that decreased antigen affinity to the BCR promotes regulatory B cell function which can be overcome by increased avidity of membrane-tethered antigen. Furthermore, soluble and membrane-tethered antigens drive qualitatively distinct germinal center, plasma cell, memory B cell, and Treg responses. Finally, we describe two classes of membrane-associated antigens that correlate with GC B cell signature and improved survival in pancreatic cancer patients. Thus, antigen localization impacts basic mechanisms governing B cell differentiation and the resulting immune response to solid malignancy with implications for vaccine engineering.
Citation Format: Colleen Sturdevant, Nancy Kren, Harrison Silva, Ismael Gomez, Austin Hepperla, Yuliya Pylayeva-Gupta. Antigenic properties determine the outcome of B cell driven anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B047.
Abstract B057: The circadian master regulator BMAL1 blocks immune cell recognition of pancreatic ductal adenocarcinomas via tumor-derived interleukin-1 receptor antagonist
Authors: Prela Orjola , Wang Lan , Harris Chris , Carpizo Darren 
Published: September 2024

Abstract
Many tumor types, including pancreatic adenocarcinomas, have dysregulated circadian rhythms. Previous work in our lab has shown that disseminated dormant tumor cells have increased expression of Dec2, a circadian rhythm gene, and knocking out Dec2 leads to increased overall survival in our murine resectable PDAC model. To see whether the effect of Dec2 is due to a circadian effect, we deleted the master regulator circadian gene, BMAL1. Using CRISPR-generated knockout (KO) cell lines, we saw that loss of Bmal1 completely abrogated metastasis in immunocompetent mice, but not in immunocompromised mice indicating an immune mediated mechanism. Similarly in our murine resectable PDAC model, loss of BMAL1 led to an increase in overall survival in immunocompetent mice only. Looking at the tumor microenvironment, we saw an increase in CD4+ and CD8+ T cell infiltration in the tumors derived from the BMAL KO cells. We then evaluated the BMAL KO cells for their cytokine secretion and saw that loss of BMAL1 led to decreased interleukin-1 receptor antagonist both in vitro and in vivo. IL-Ra has been shown in literature to suppress the immunogenic anti-tumor response by impairing the activities of APCs, CD4+ and CD8+ T cells and disruption of IL-1Ra can reverse the TME towards more immunogenic leading to an antitumor effect. Taken together these studies implicate Bmal1 in regulating anti-tumor immunity in PDAC through its regulation of IL-1Ra secretion. This is a novel function for a circadian rhythm gene in PDAC biology.
Citation Format: Orjola Prela, Lan Wang, Chris Harris, Darren Carpizo. The circadian master regulator BMAL1 blocks immune cell recognition of pancreatic ductal adenocarcinomas via tumor-derived interleukin-1 receptor antagonist [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B057.
Abstract B060: Unveiling resistance mechanisms to CAR T-cell therapy in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening
Authors: Fröse Julia , Whittaker Charlie , Leclerc Paul , Langenbucher Adam , Hellinger Riley , Goulet Daniel R. , Hemann Michael T. 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death by 2030. PDAC lacks effective treatment options and innovative strategies for therapeutic intervention are urgently needed. Chimeric Antigen Receptor (CAR)-T cell therapy has shown remarkable success in treating hematologic malignancies, yet achieving efficacy in solid tumors remains a significant challenge. Early results from clinical trials show limited efficacy of CAR T-cell therapy in PDAC. To uncover tumor-intrinsic mechanisms of resistance to CAR T-cell therapy in vivo, we performed iterative CRISPR/Cas9-based pooled screens in a fully immunocompetent, orthotopic model of PDAC. We identified a variety of genes influencing CAR T-cell treatment efficacy. In particular, loss of genes involved in redox biology and oxidative stress sensitized PDAC tumors to CAR T-cell therapy in vivo. Additionally, single-cell RNA sequencing of PDAC tumors subjected to CAR T-cell therapy unveiled a distinct subset of tumor cells resilient to the treatment, characterized by changes in oxidative stress. Our findings indicate a potential avenue for therapeutic synergy by targeting pathways involved in oxidative stress to increase the efficacy of CAR T cell therapy in PDAC.
Citation Format: Julia Fröse, Charlie Whittaker, Paul Leclerc, Adam Langenbucher, Riley Hellinger, Daniel R. Goulet, Michael T. Hemann. Unveiling resistance mechanisms to CAR T-cell therapy in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B060.
Abstract B064: Antigen-presenting type-I conventional dendritic cells facilitate curative checkpoint blockade immunotherapy in pancreatic cancer
Authors: Mahadevan Krishnan K , Dyevoich Allison M. , Chen Yang , Li Bingrui , Sugimoto Hikaru , Sockwell Amari , McAndrews Kathleen , Wang Huamin , Shalapour Shabnam , Watowich Stephanie , Kalluri Raghu 
Published: September 2024

Abstract
The link between cancers and inflammation was first made by Rudolph Virchow more than a century ago when cancers were observed at sites with chronic inflammation. The host response to cancer shares many parallels with inflammation and wound healing process.Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type-I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and eradication of ptPDAC with restoration of lifespan even upon PDAC re-challenge. Such eradication of ptPDAC was reversed following specific depletion of dendritic cells. Employing PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with a curative outcome. Analysis of the T-cell receptor (TCR) sequences in the tumor infiltrating CD8+ T cells following cDC1 vaccination coupled with iCBT identified unique CDR3 sequences with potential therapeutic significance. Our findings identify a fundamental difference in the immune microenvironment and adaptive immune response in PDAC concurrent with, or without pancreatitis, and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.
Citation Format: Krishnan K Mahadevan, Allison M. Dyevoich, Yang Chen, Bingrui Li, Hikaru Sugimoto, Amari Sockwell, Kathleen McAndrews, Huamin Wang, Shabnam Shalapour, Stephanie Watowich, Raghu Kalluri. Antigen-presenting type-I conventional dendritic cells facilitate curative checkpoint blockade immunotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B064.