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Integrins mediate adhesive interactions between cells and their environment, including neighboring cells and extracellular matrix (ECM). These heterodimeric transmembrane receptors bind extracellular ligands with their globular head domains and connect to the cytoskeleton through multi-protein interactions at their cytoplasmic tails. Integrin containing cell–matrix adhesions are dynamic force-responsive protein complexes that allow bidirectional mechanical coupling of cells with their environment. This allows cells to sense and modulate tissue mechanics and regulates intracellular signaling impacting on cell faith, survival, proliferation, and differentiation programs. Dysregulation of these functions has been extensively reported in cancer and associated with tumor growth, invasion, angiogenesis, metastasis, and therapy resistance. This central role in multiple hallmarks of cancer and their localization on the cell surface makes integrins attractive targets for cancer therapy. However, despite a wealth of highly encouraging preclinical data, targeting integrin adhesion complexes in clinical trials has thus far failed to meet expectations. Contributing factors to therapeutic failure are 1) variable integrin expression, 2) redundancy in integrin function, 3) distinct roles of integrins at various disease stages, and 4) sequestering of therapeutics by integrin-containing tumor-derived extracellular vesicles. Despite disappointing clinical results, new promising approaches are being investigated that highlight the potential of integrins as targets or prognostic biomarkers. Improvement of therapeutic delivery at the tumor site via integrin binding ligands is emerging as another successful approach that may enhance both efficacy and safety of conventional therapeutics. In this review we provide an overview of recent encouraging preclinical findings, we discuss the apparent disagreement between preclinical and clinical results, and we consider new opportunities to exploit the potential of integrin adhesion complexes as targets for cancer therapy.

Treatment with adoptively transferred T cells is challenged by limited longevity of therapeutic cells within tumors. To enhance the durability of anti-tumor T cell products, we have created T cell receptors (TCRs) with built-in co-stimulatory molecules. We observed that TCRs coupled to ICOS mediated exceptionally long-term responses including delay of tumor recurrence and cures in a mouse tumor model. TCR:ICOS T cells showed enhanced and antigen-specific production of inflammatory cytokines and resistance to exhaustion. Genetic ablation of ICOS-mediated activation of the PI3K-NFκB pathway neutralized the long-term anti-tumor effects. To translate TCR:ICOS to human T cells, we identified a single amino acid change in the cytosolic tail which was necessary for functional surface expression. Notably, the optimized receptor sustained performance of human T cells upon repeated stimulation across multiple antigen specificities. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy. Newly designed co-stimulatory TCR, with extracellular TCR-V and C domains coupled to CD28 transmembrane domain, and ICOS and CD3ε intracellular domains (in short TCR:ICOS) provides: ➢durable anti-tumor response and T cell persistence in mouse model➢inflammatory T cell phenotype and resistance to T cell exhaustion➢effects via PI3K and NFκB activation➢translation to human T cells upon single amino acid mutation in TCR:ICOS tail➢extension to multiple clinically relevant TCRs while preserving prolonged T cell fitness durable anti-tumor response and T cell persistence in mouse model inflammatory T cell phenotype and resistance to T cell exhaustion effects via PI3K and NFκB activation translation to human T cells upon single amino acid mutation in TCR:ICOS tail extension to multiple clinically relevant TCRs while preserving prolonged T cell fitness

Triple-negative breast cancer (TNBC) shows an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T-cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naive repertoires. Following gene introduction into T-cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize non-cognate epitopes from alternative source proteins. Notably, this TCR mediated killing of three-dimensional tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T-cells as a treatment for the vast majority of TNBC patients.Competing Interest StatementThis research was conducted according to the requirements of objectivity and integrity standards. DH is listed as inventor for European patent application no. P128827EP00. MK has received research support from BMS, Roche, AstraZeneca, personal fees from AstraZeneca, Daiichi Sankyo, Domain Therapeutics, Alderaan, BMS, MSD, Gilead, Roche outside the submitted work (all paid to the NKI/AVL). RD has received research support from MSD and Bayer, personal fees from Bluebird Bio, Genticel, other support from Pan Cancer T B.V. outside the submitted work (all paid to the Erasmus MC Cancer Institute) and is listed as inventor for European patent applications P130556EP00 and P128827EP00. All other authors (DK, MvB, RW, DR, KK, MT, CYL, ATJ, RF, JM, MdB, SIB, JAD, MK, EHJD, MBS, JWM, RJMA) declare no competing interests.

Leptographium wageneri is a native fungal pathogen in western North America that causes black stain root disease (BSRD) of conifers. Three host-specialized varieties of this pathogen were previously described: L. wageneri var. wageneri on pinyon pines ( Pinus monophylla and P . edulis ); L. wageneri var. ponderosum , primarily on hard pines (e.g., P . ponderosa , P . jeffreyi ); and L. wageneri var. pseudotsugae on Douglas-fir ( Pseudotsuga menziesii ). Morphological, physiological, and ecological differences among the three pathogen varieties have been previously determined; however, DNA-based characterization and analyses are needed to determine the genetic relationships among these varieties. The objective of this study was to use DNA sequences of 10 gene regions to assess phylogenetic relationships among L. wageneri isolates collected from different hosts. The multigene phylogenetic analyses, based on maximum likelihood and Bayesian inference, strongly supported species-level separation of the three L. wageneri varieties. These results, in conjunction with previously established phenotypic differences, support the elevation of L. wageneri var. ponderosum and L. wageneri var. pseudotsugae to the species level as L . ponderosum comb. nov. and L . pseudotsugae comb. nov., respectively, while maintaining L. wageneri var. wageneri as Leptographium wageneri . Characterization of the three Leptographium species, each with distinct host ranges, provides a baseline to further understand the ecological interactions and evolutionary relationships of these forest pathogens, which informs management of black stain root disease.

Background:In our previous Sjögren’s Disease (SjD) Genome-Wide Association Study (GWAS) in European populations, significant single nucleotide polymorphism (SNP) peaks were identified between PRDM1 and ATG5 [1]. ATG5 is an autophagy-related protein that plays a crucial role in neutrophil extracellular trap (NET) formation, degranulation, and limiting autoantigens in blood. Dysregulated autophagy has been implicated in SjD and systemic lupus erythematosus (SLE) pathology and poor disease outcomes [2, 3]. The transcriptional repressor PRDM1 plays a role in regulating lymphocyte differentiation [4].Objectives:Identify and functionally evaluate SjD and SLE risk variants in the PRDM1-ATG5 risk locus.Methods:By conducting a meta-analysis of SjD and SLE GWAS datasets, we defined a credible SNP set in the PRDM1-ATG5 locus. A GWAS involving 15,691 SjD and SLE cases and 52,521 population controls of European ancestry was performed, and SNP-trait associations were tested using logistic regression models in PLINK. Bioinformatic analyses (RegulomeDB, HaploReg v4.2, promoter capture Hi-C, eQTLs, etc.) further prioritized SNPs. A CRISPR inhibition (CRISPRi) assay was used to assess the effects of these SNPs on ATG5 expression. Luciferase assays in A235 salivary gland epithelial cell line, PLB985 malignant myelomonoblasts, and GM12878 EBV-transformed B cells tested the activation and/or repressive activity of candidate SNPs.Results:Our investigation revealed several candidate functional SNPs within the PRDM1-ATG5 region. Among them, rs533733 (p=1.15E-18), rs34582442 (p=2.79E-08), rs34599047 (p=2.82E-08), rs77846660 (p=8.39E-04), and rs56886418 (p=4.23E-03) emerged as noteworthy, suggesting their involvement in the regulatory landscape of this locus. Expanding our focus, the inclusion of rs1152966 (p=3.39E-15), rs11152964 (p=7.18E-11), rs573775 (p=6.13E-06), and rs12175062 (p=2.67E-03) in the analysis revealed a broader understanding of eQTLs and chromatin accessibility and modification patterns associated with these SNPs. The extensive influence of these SNPs was observed across various cell types, including minor salivary glands and blood cells, emphasizing their relevance in the pathogenesis of SjD and SLE. Functional assays further elucidated the allele-specific effects of selected SNPs. Notably, rs56885418 and rs3804333 demonstrated a significant decrease in enhancer activity, while rs533733 and rs62422881 exhibited an increase in enhancer activity, particularly in the A253 cell line. These findings underscore the dynamic regulatory impact of these SNPs on gene expression, providing valuable insights into the molecular mechanisms at play in the PRDM1-ATG5 locus.Conclusion:Functional characterization of SNPs in the PRDM1-ATG5 locus provides new insights into the regulatory mechanisms governing gene expression in SjD and SLE. Ongoing studies will focus on in vitro validation of predicted functional SNPs in A235 and GM12878 cells.REFERENCES:[1] Khatri B, et al. Nat Commun. 2022 Jul;13(1):4287.[2] Byun YS, et al. Sci Rep. 2017 Dec;7(1):17280.[3] Wible DJ, et al. Cell Discov. 2019; 5:42.[4] Kallies A, Nutt SL. Curr Opin Immunol. 2007 Apr;19(2):156-62.Acknowledgements:National Institutes of Health (NIH): R01AR071410, R01AR073855, R01AR065953, P50AR060804, U01DE028891; National Research Foundation of Korea (NRF-2021R1A6A1A03038899); Sjögren’s Foundation; Presbyterian Health Foundation; Jerome L. Greene Foundation.Disclosure of Interests:Marcin Radziszewski: None declared, Mandi M Wiley: None declared, Bhuwan Khatri: None declared, Astrid Rasmussen: None declared, Kandice L Tessneer: None declared, Kwangwoo Kim: None declared, Edward M. Vital: None declared, Nick Dand: None declared, Chen Gong: None declared, David Morris: None declared, Phil Tombleson: None declared, Elena Pontarini: None declared, Michele Bombardieri: None declared, Maureen Rischmueller: None declared, Marie Wahren-Herlenius: None declared, Marika Kvarnström: None declared, Torsten Witte: None declared, Hendrika Bootsma: None declared, Gwenny M. Verstappen: None declared, Frans G.M. Kroese: None declared, Arjan Vissink: None declared, Sarah Pringle: None declared, Athanasios Tzioufas: None declared, Clio Mavragani: None declared, Alan Baer Received consulting fees from Bristol Myers Squibb (BMS) and iCell Gene Therapeutics., Marta Alarcon-Riquelme: None declared, Javier Martin: None declared, Xavier Mariette: None declared, Gaetane Nocturne: None declared, Jacques-Olivier Pers: None declared, Jacques-Eric Gottenberg: None declared, Wan-Fai Ng I have consulted for Novartis, BMS, Janssen, Sanofi, Abbvie, IQVIA, Argenx, Resolve Therapeutics., Caroline Shiboski: None declared, Kimberly E Taylor: None declared, Lindsey Criswell: None declared, Blake M Warner: None declared, A Darise Farris Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023)., Patrick M Gaffney: None declared, Judith A. James: None declared, R Hal Scofield Received consulting fees from Johnson and Johnson Innovative Medicine (formerly Janssen) and Merk Pharmaceuticals., Joel M Guthridge: None declared, Daniel J Wallace: None declared, Swamy Venuturupali: None declared, Michael T Brennan: None declared, Juliana Imgenberg-Kreuz: None declared, Lars Ronnblom: None declared, Eva Baecklund: None declared, Maija-leena Eloranta: None declared, Lara A Aqrawi: None declared, Øyvind Palm: None declared, Johan G Brun: None declared, Daniel Hammenfors: None declared, Malin V Jonsson: None declared, Silke Appel: None declared, Sara Magnusson Bucher: None declared, Helena Forsblad-d’Elia: None declared, Thomas Mandl Employee of UCB., Per Eriksson: None declared, Sang-Cheol Bae: None declared, Timothy J Vyse: None declared, Betty Tsao: None declared, Gunnel Nordmark: None declared, Christopher J Lessard Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023).

Fusarium crown rot (FCR) of winter wheat (Triticum aestivum L.), caused by Fusarium pseudograminearm and Fusarium culmorum, is a yield‐limiting disease in arid wheat‐producing areas of the inland Pacific Northwest. Foliar fungicide applications and currently available seed treatments do not control FCR. Alternative crops that provide a rotational benefit to reduce disease are not economically feasible. Major‐gene resistance is unavailable, but there is preliminary evidence that some wheat and barley (Hordeum vulgare L.) cultivars are more resistant than others. We followed up on preliminary work by growing 14 varieties of winter wheat, planted with in‐furrow FCR inoculum, in 2018 and 2019 in Morrow County, Oregon—one of the world's driest wheat producing regions. Two barley cultivars were added to the experiment during the second year of research. Evaluations of cultivar resistance were made by conducting aboveground visual assessments by counting whiteheads, prematurely senesced wheat heads that are indicative of FCR infection. Whitehead count information was correlated with yield and grain volume weight data. Maximum whitehead counts were measured in plots of the FCR‐susceptible check cultivar ‘Stephens’. There was no evidence of a cultivar‐specific relationship between whitehead count and corresponding values for yield and grain volume weight. There was limited evidence that some cultivars have the capacity to compensate for effects of disease. Core Ideas There is evidence that some wheat cultivars have the capacity to compensate for Fusarium crown rot (FCR). It is necessary to corroborate whitehead counts with FCR symptomology on crown tissue. The contradiction of whitehead count data and yield may be due to increased tillering capacity.