Johnson, A. M. | bioRxiv Science

bioRxiv2019

Adaptations of Atribacteria to life in methane hydrates: hot traits for cold life

Gas hydrates harbor gigatons of natural gas, yet their microbiomes remain understudied. We bioprospected 16S rRNA amplicons, metagenomes, and metaproteomes from methane hydrate-bearing sediments under Hydrate Ridge (offshore Oregon, USA, ODP Site 1244, 2-69 mbsf) for novel microbial metabolic and biosynthetic potential. Atribacteria sequences generally increased in relative sequence abundance with increasing sediment depth. Most Atribacteria ASVs belonged to JS-1-Genus 1 and clustered with other sequences from gas hydrate-bearing sediments. We recovered 21 metagenome-assembled genomic bins spanning three geochemical zones in the sediment core: the sulfate-methane transition zone, metal (iron/manganese) reduction zone, and gas hydrate stability zone. We found evidence for bacterial fermentation as a source of acetate for aceticlastic methanogenesis and as a driver of iron reduction in the metal reduction zone. In multiple zones, we identified a Ni-Fe hydrogenase-Na+/H+ antiporter supercomplex (Hun) in Atribacteria and Firmicutes bins and in other deep subsurface bacteria and cultured hyperthermophiles from the Thermotogae phylum. Atribacteria expressed tripartite ATP-independent (TRAP) transporters downstream from a novel regulator (AtiR). Atribacteria also possessed adaptations to survive extreme conditions (e.g., high salt brines, high pressure, and cold temperatures) including the ability to synthesize the osmolyte di-myo-inositol-phosphate as well as expression of K+-stimulated pyrophosphatase and capsule proteins. Originality-Significance StatementThis work provides insights into the metabolism and adaptations of microbes that are ubiquitous and abundant in methane-rich ecosystems. Our findings suggest that bacterial fermentation is a source of acetate for aceticlastic methanogenesis and a driver of iron reduction in the metal reduction zone. Atribacteria, the most abundant phylum in gas hydrate-bearing sediments, possess multiple strategies to cope with environmental stress.

microbiology↗

bioRxiv2019

Tumor-Intrinsic Response to IFNgamma Shapes the Tumor Microenvironment and Anti-PD-1 Response in NSCLC

Targeting PD-1/ PD-L1 is only effective in ~20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated while LLC tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA-Seq analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFN{gamma} signature that was absent in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFN{gamma} and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of Socs1, an inhibitor of IFN{gamma}. Silencing Socs1 increased response to IFN{gamma} in vitro and sensitized tumors to anti-PD-1. This was associated with a reshaped TME, characterized by enhanced T cell infiltration and enrichment of PD-L1 high myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFN{gamma} signaling can induce of cascade of changes associated with increased therapeutic vulnerability. SummaryMechanisms regulating response to anti-PD-1 therapy in lung cancer are not well defined. This study, using orthotopic immunocompetent mouse models of lung cancer, demonstrates that intrinsic sensitivity of cancer cells to IFN{gamma} determines anti-PD-1 responsiveness through alterations in the tumor microenvironment.

cancer biology↗