Biology subjects

Kaufman, A. J.

Publications and source records attributed to Kaufman, A. J..

2 recordsLinked to original sources

bioRxiv2024

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors

ABSTRACTMonocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

immunology↗

bioRxiv2020

Were Neoarchean atmospheric methane hazes and early Paleoproterozoic glaciations driven by the rise of oxygen in surface environments?

Geochemical evidence suggests methane was the predominant greenhouse gas in the Archean and early Proterozoic eons. Consequently, fluctuations in methane concentration in Earths atmosphere (i.e., methane hazes) would have contributed to climate change and influenced the flux of UV radiation reaching surface environments. If correct, understanding what factors (e.g., O2 and/or resource concentration) drove the biological methane cycle might shed light on the repetition of biological, atmospheric and climatic events preserved in the sedimentary rock record from ~2.8 to 2.0 BYA. To explore these interdependencies, we developed a novel dynamical model of microbial ecological interactions to investigate the conditions under which methane is preferentially released to the atmosphere. We found that the interplay between resource and O2 availability results in complex cyclic methane dynamics unrelated to the functional groups or efficiencies of microbial communities, to initial conditions, or to other model constraints. Based on these results, we propose that the cyclicity of methane haze events and glacial episodes in the Neoarchean and early Paleoproterozoic may have been linked to the progressive increase in oceanic and atmospheric O2 through the interval.

systems biology↗