Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions

Abstract: Background and aims: Kupffer cells (KCs), the resident tissue macrophages of the liver, play a crucial role in the clearance of pathogens and other particulate materials that reach the systemic circulation. Recent studies have identified KCs as a yolk sac-derived resident macrophage population that is replenished independently of monocytes in the steady state. Although it is now established that following local tissue injury, bone-marrow derived monocytes may infiltrate the tissue and differentiate into macrophages, the extent to which newly differentiated macrophages functionally resemble the KCs they have replaced has not been extensively studied. Methods and results: Here we show using intravital microscopy, morphometric analysis and gene expression profiling that bone marrow derived “KCs” accumulating as a result of genotoxic injury resemble, but are not identical to their yolk-sac (YS) counterparts. An ion homeostasis gene signature, including genes associated with scavenger receptor function and extracellular matrix deposition, allows discrimination between these two KC populations. Reflecting the differential expression of scavenger receptors, YS-derived KCs were more effective at accumulating Ac-LDL, whereas surprisingly they were poorer than BM-derived KCs when assessed for uptake of a range of bacterial pathogens. The two KC populations were almost indistinguishable in regard to i) response to LPS challenge, ii) phagocytosis of effete RBCs and iii) their ability to contain infection and direct granuloma formation against Leishmania donovani, a KC-tropic intracellular parasite. Conclusions: BM-derived KCs differentiate locally to resemble YS-derived KC in most but not all respects, with implications for models of infectious diseases, liver injury and bone marrow transplantation. In addition, the gene signature we describe adds to the tools available for distinguishing KC subpopulations based on their ontology

Phosphoantigen-Stimulated gamma delta T Cells Suppress Natural Killer-Cell Responses to Missing-Self

gamma delta T cells stimulated by phosphoantigens (pAg) are potent effectors that secrete Th1 cytokines and kill tumor cells. Consequently, they are considered candidates for use in cancer immunotherapy. However, they have proven only moderately effective in several clinical trials. We studied the consequences of pAg-stimulated gamma delta T-cell interactions with natural killer (NK) cells and CD8(+) T cells, major innate and adaptive effectors, respectively. We found that pAg-stimulated gamma delta T cells suppressed NK-cell responses to ``missing-self'' but had no effect on antigen-specific CD8(+) T-cell responses. Extensive analysis of the secreted cytokines showed that pAg-stimulated gamma delta T cells had a proinflammatory profile. CMV-pp65-specific CD8(+) T cells primed with pAg-stimulated gamma delta T cells showed little effect on responses to pp65-loaded target cells. By contrast, NK cells primed similarly with gamma delta T cells had impaired capacity to degranulate and produce IFN gamma in response to HLA class I-deficient targets. This effect depended on BTN3A1 and required direct contact between NK cells and gamma delta T cells. gamma delta T-cell priming of NK cells also led to a downregulation of NKG2D and NKp44 on NK cells. Every NK-cell subset was affected by gamma delta T cell-mediated immunosuppression, but the strongest effect was on KIR(+)NKG2A(-) NK cells. We therefore report a previously unknown function for gamma delta T cells, as brakes of NK-cell responses to ``missing-self.'' This provides a new perspective for optimizing the use of gamma delta T cells in cancer immunotherapy and for assessing their role in immune responses to pAg-producing pathogens

Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade

© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.This work was supported by a Cancer Research UK Institute Award (A19258) to S.Z. We thank colleagues at CRUK Manchester Institute core facilities, in particular, Biological Resource Unit, Transgenic Breeding, Molecular Biology, Histology, and Flow Cytometry. E.B. was supported by an EMBO long-term fellowship ( ALTF-69-2016 ) and an EMBO advanced fellowship ( aALTF-638-2018 ). C.P.B. was funded by the National Institute for Health Research Manchester Biomedical Research Centre . G.J. was supported by a scholarship from The Society of Swedish Engineers in Great Britain . K.W.-B. was supported by a doctoral studentship from the Medical Research Council . C.R.e.S. was supported by The Francis Crick Institute , which receives core funding from Cancer Research UK ( FC001136 ), the UK Medical Research Council ( FC001136 ), and the Wellcome Trust ( FC001136 ), by an ERC Advanced Investigator grant ( AdG 268670 ), by a Wellcome Investigator Award ( WT106973MA ), and by a prize from the Louis-Jeantet Foundation . N.G. was supported by an Imperial Confidence in Concept Scheme ( RSRO_P71752 ). D.M.D. was supported by a Wellcome Trust Investigator Award ( 110091/Z/15/Z ).info:eu-repo/semantics/publishedVersio