Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment.

BACKGROUND: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. RESULTS: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. CONCLUSIONS: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing.

Host-directed therapy with 2-deoxy-D-glucose inhibits human rhinoviruses, endemic coronaviruses, and SARS-CoV-2.

Rhinoviruses (RVs) and coronaviruses (CoVs) upregulate host cell metabolic pathways such as glycolysis to meet their bioenergetic demands for rapid multiplication. Using the glycolysis inhibitor 2-deoxy-d-glucose (2-DG), we assessed the dose-dependent inhibition of viral replication of minor- and major-receptor group RVs in epithelial cells. 2-DG disrupted RV infection cycle by inhibiting template negative-strand as well as genomic positive-strand RNA synthesis, resulting in less progeny virus and RV-mediated cell death. Assessment of 2-DG's intracellular kinetics revealed that after a short-exposure to 2-DG, the active intermediate, 2-DG6P, is stored intracellularly for several hours. Finally, we confirmed the antiviral effect of 2-DG on pandemic SARS-CoV-2 and showed for the first time that it also reduces replication of endemic human coronaviruses. These results provide further evidence that 2-DG could be used as a broad-spectrum antiviral.

Genome characterization of a novel megrivirus-related avian picornavirus from a carnivorous wild bird, western marsh harrier (Circus aeruginosus).

In this study, the complete genome of a novel picornavirus called harrier picornavirus 1 (HaPV-1) strain harrier/MR-01/HUN/2014 (KY488458) was sequenced and analysed from a cloacal sample of a threatened, carnivorous wild bird, western marsh harrier (Circus aeruginosus). HaPV-1 was detectable from 2 of the 3 samples from harriers. HaPV-1 is phylogenetically related to megriviruses (genus Megrivirus) from domestic chicken, turkey and duck, showing a similar genome organization pattern; it also has an avian picornavirus-like "Unit A" motif in the 3' UTR. Unlike the type-IV internal ribosomal entry site (IRES) of megriviruses, HaPV-1 is predicted to contain a type-II-like IRES, suggesting modular exchange of IRES elements between picornavirus genomes.

A diarrheic chicken simultaneously co-infected with multiple picornaviruses: Complete genome analysis of avian picornaviruses representing up to six genera.

In this study all currently known chicken picornaviruses including a novel one (chicken phacovirus 1, KT880670) were identified by viral metagenomic and RT-PCR methods from a single specimen of a diarrheic chicken suffering from a total of eight picornavirus co-infections, in Hungary. The complete genomes of six picornaviruses were determined and their genomic and phylogenetic characteristics and UTR RNA structural models analyzed in details. Picornaviruses belonged to genera Sicinivirus (the first complete genome), Gallivirus, Tremovirus, Avisivirus and "Orivirus" (two potential genotypes). In addition, the unassigned phacoviruses were also detected in multiple samples of chickens in the USA. Multiple co-infections promote and facilitate the recombination and evolution of picornaviruses and eventually could contribute to the severity of the diarrhea in chicken, in one of the most important food sources of humans.

Genome characterization of a novel chicken picornavirus distantly related to the members of genus Avihepatovirus with a single 2A protein and a megrivirus-like 3' UTR.

The members of the genus Avihepatovirus and related picornaviruses ("Aalivius") of ducks, turkey and chickens possess identical 2A peptide composition including three functionally unrelated 2A peptides which is a characteristic genome feature of these monophyletic avian picornaviruses. The complete genome of a novel picornavirus provisionally named Orivirus A1 (KM203656) from a cloacal sample of a 4-week-old diarrheic chicken (Gallus gallus domesticus) distantly related to members of genus Avihepatovirus was characterized. The study strain contains a type-II-like IRES, a single 2A protein of unknown function unrelated to the 2A proteins of avihepatoviruses and a long 3' untranslated region (UTR) with multiple repeated sequence motifs followed by an AUG-rich region. The repeated sequences of the 3' UTR show significant identity to the "Unit A" sequences of the phylogenetically distant megriviruses. The presence of a novel single 2A and the megrivirus-like "Unit A" motifs suggest multiple recombination events in the evolution of this novel picornavirus.