Abstract B035: Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer
Kelly D. DeMarcoLoretah ChibayaChristina F. LusiGriffin KaneMeghan L. BrassilChaitanya N. ParikhKatherine MurphyShreya R ChowduryJunhui LiBoyang MaTiana E TaylorJulia CerruttiHaruka MoriMiranda Diaz-InfanteJessica PeuraJason R. PitarresiLihua Julie ZhuKatherine A. FitzgeraldPrabhani U. AtukoraleMarcus Ruscetti
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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.Keywords:
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To identify senescence‐associated genes (SAGs) in rice leaves, senescence was induced by transferring rice seedlings into darkness. Senescence up‐regulated cDNAs were obtained by PCR‐based subtractive hybridization. Among 14 SAG clones characterized, 11 were found to be associated with both dark‐induced and natural leaf senescence. Three clones were associated only with dark‐induced leaf senescence. The possible physiological roles of these SAGs during rice leaf senescence are discussed.
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The mechanisms of cell senescence mainly contain exterior oxidative stress theory and interior senescence-associated genes regulation theory.In recent years,the research on cell senescence pathway induced by reactive oxygen species and the regulation of senescence-associated genes,like p16,p53/p21 gains significant progress,clarifying the mechanisms of cell senescence further.With the extension of the knowledge on cell senescence,the projects on the profound benefits of cell senescence and on the relationship between cell senescence and individual aging,tumorigenesis have also drawn more and more attention.
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Wheat leaf senescence is a developmental process that involves expressional changes in thousands of genes that ultimately impact grain protein content (GPC), grain yield (GY), and nitrogen use efficiency. The onset and rate of senescence are strongly influenced by plant hormones and environmental factors e.g. nitrogen availability. At maturity, decrease in nitrogen uptake could enhance N remobilization from leaves and stem to grain, eventually leading to leaf senescence. Early senescence is related to high GPC and somewhat low yield whereas late senescence is often related to high yield and somewhat low GPC. Early or late senescence is principally regulated by up and down-regulation of senescence associated genes. Integration of external and internal factors together with genotypic variation influence senescence associated genes in a developmental age dependent manner. Although regulation of genes involved in senescence has been studied in rice, Arabidopsis, maize, and currently in wheat, there are genotype-specific variations yet to explore. A major effort is needed to understand the interaction of positive and negative senescence regulators in determining the onset of senescence. In wheat, increasing attention has been paid to understand the role of positive senescence regulator, e.g. GPC-1, regulated gene network during early senescence time course. Recently, gene regulatory network involved early to late senescence time course revealed important senescence regulators. However, the known negative senescence regulator TaNAC-S gene has not been extensively studied in wheat and little is known about its value in breeding. Existing data on senescence-related transcriptome studies and gene regulatory network could effectively be used for functional study in developing nitrogen efficient wheat varieties.
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Cellular senescence is a complex process associated with irreversible cell cycle arrest. We can distinguish replicative senescence, which is telomere dependent and stress-induced premature senescence (SIPS), which is telomere independent. Replicative senescence can be observed in culture after a few weeks or months, depending on the cell type. On the other hand SIPS can be observed a few days after treating with a senescence inducing agent. Till now a universal marker of senescence has not been decribed. Studies concerning senescence are possible thanks to the existance of many markers of senescence which enable to observe molecular as well as biochemical changes associated with this process. The presence of a few markers of senescence allows us to be sure that cells underwent senescence.
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In addition to age and developmental progress, leaf senescence and senescence-associated genes (SAGs) can be induced by other factors such as plant hormones, pathogen infection and environmental stresses. The relationship is not clear, however, between these induced senescence processes and developmental leaf senescence, and to what extent these senescence-promoting signals mimic age and developmental senescence in terms of gene expression profiles. By analysing microarray expression data from 27 different treatments (that are known to promote senescence) and comparing them with that from developmental leaf senescence, we were able to show that at early stages of treatments, different hormones and stresses showed limited similarity in the induction of gene expression to that of developmental leaf senescence. Once the senescence process is initiated, as evidenced by visible yellowing, generally after a prolonged period of treatments, a great proportion of SAGs of developmental leaf senescence are shared by gene expression profiles in response to different treatments. This indicates that although different signals that lead to initiation of senescence may do so through distinct signal transduction pathways, senescence processes induced either developmentally or by different senescence-promoting treatments may share common execution events.
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SUMMARY Leaf senescence is a hiphly‐controlled sequence of events comprising the final stage of development. Cells remain viable during the process and new gene expression is required. There is some similarity between senescence in plants and programmed cell death in animals. In this review, different classes of senescence‐related genes are defined and progress towards isolating such genes is reported. A range of internal and external factors which appear to cause leaf senescence is considered and various models for the mechanism of senescence‐ initiation are described. The current understanding of senescence at the wrganelle and molecular levels is presented. Finally, same ideas are mooted as to why senescence occurs and why it should be studied further. Contents Summary 419 I. Introduction 420 II. Internal factors that cause senescence 423 III. External factors that cause senescence 427 IV. What is the mechanism of senescence initiation? 428 V. Progress in the understanding of organelle senescence 431 VI. Progress in the understanding of senescence at the molecular level 434 VII. The control of senescence in animals and plants 440 VIII. Why is senescence necessary? 441 IX. Why study senescence? 441 References 442
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