Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.

Monocyte-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.

Functional impairment of "helpless" CD8 + memory T cells is transient and driven by prolonged but finite cognate antigen presentation.

Generation of functional CD8 + T cell memory typically requires engagement of CD4 + T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (T E ) and subsequent memory (T M ) CD8 + T cell formation appear impervious to a lack of CD4 + T cell help during priming. Nonetheless, such "helpless" CD8 + T M respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8 + T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8 + T E differentiation is largely normal but a multiplicity of helpless CD8 T M defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8 + T M potential and recall capacity. Our findings provide a unified explanation for helpless CD8 + T cell memory and emphasize an unexpected CD8 + T M plasticity with implications for vaccination strategies and beyond.