PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific versus T cell–specific PD-1 ablation on antitumor immunity has remained unclear because most studies have used either PD-1–blocking antibodies or complete PD-1 KO mice. We generated a conditional allele, which allowed myeloid-specific (PD-1f/fLysMcre) or T cell–specific (PD-1f/fCD4cre) targeting of Pdcd1 gene. Compared with T cell–specific PD-1 ablation, myeloid cell–specific PD-1 ablation more effectively decreased tumor growth. We found that granulocyte/macrophage progenitors (GMPs), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSCs), express PD-1. In tumor-bearing PD-1f/fLysMcre but not PD-1f/fCD4cre mice, accumulation of GMP and MDSC was prevented, whereas systemic output of effector myeloid cells was increased. Myeloid cell–specific PD-1 ablation induced an increase of T effector memory cells with improved functionality and mediated antitumor protection despite preserved PD-1 expression in T cells. In PD-1–deficient myeloid progenitors, growth factors driving emergency myelopoiesis induced increased metabolic intermediates of glycolysis, pentose phosphate pathway, and TCA cycle but, most prominently, elevated cholesterol. Because cholesterol is required for differentiation of inflammatory macrophages and DC and promotes antigen-presenting function, our findings indicate that metabolic reprogramming of emergency myelopoiesis and differentiation of effector myeloid cells might be a key mechanism of antitumor immunity mediated by PD-1 blockade.

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Although the microbiota is considered to be the primary source of off-flavors in farmed fish, there is a lack of information about the possible contribution of feeds to fish malodor. For this reason, the current study was designed to perform comprehensive sensory and chemo-analytical characterization of fish feed constituents that can impact the quality of farmed fish, and to determine whether feeds cause malodor accumulation in fish. To this aim, odorants in four commercial fish feeds were extracted using solvent assisted flavor evaporation (SAFE) and characterized by comparative aroma extract dilution analysis (cAEDA) and multi-dimensional gas chromatography-mass spectrometry/olfactometry (MD-GC-MS/O). The odorants in the fish feed samples were correlated with their respective sensory and fatty acid profiles. The cAEDA studies revealed the presence of 81 odorants of which 55 compounds were common to all the samples. Most of these odorants are identified here for the first time in fish feeds, and include skatole, indole, (E,Z,Z)-2,4,7-tridecatrienal, 4-ethyloctanoic acid, and cresols. Additionally, geosmin and 3-isopropyl-2-methoxypyrazine, known for their contribution to fish taint, and other cyanobacterial by-products, dimethyldisulfide and dimethyltrisulfide, were identified in feed samples. The results suggest that fish feed may contribute to fish malodor. Most of these off-flavors were linked to lipid source (fish oil or plant/lard alternatives), unsaturated fatty acids contents, and protein type (plant-based or fishmeal-based sources) in the feed.

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The inhibitory receptor PD-1 suppresses T cell activation by recruiting the phosphatase SHP-2. However, mice with a T-cell-specific deletion of SHP-2 do not have improved antitumor immunity. Here we showed that mice with conditional targeting of SHP-2 in myeloid cells, but not in T cells, had diminished tumor growth. RNA sequencing (RNA-seq) followed by gene set enrichment analysis indicated the presence of polymorphonuclear myeloid-derived suppressor cells and tumor-associated macrophages (TAMs) with enriched gene expression profiles of enhanced differentiation, activation and expression of immunostimulatory molecules. In mice with conditional targeting of PD-1 in myeloid cells, which also displayed diminished tumor growth, TAMs had gene expression profiles enriched for myeloid differentiation, activation and leukocyte-mediated immunity displaying >50% overlap with enriched profiles of SHP-2-deficient TAMs. In bone marrow, GM-CSF induced the phosphorylation of PD-1 and recruitment of PD-1-SHP-2 to the GM-CSF receptor. Deletion of SHP-2 or PD-1 enhanced GM-CSF-mediated phosphorylation of the transcription factors HOXA10 and IRF8, which regulate myeloid differentiation and monocytic-moDC lineage commitment, respectively. Thus, SHP-2 and PD-1-SHP-2 signaling restrained myelocyte differentiation resulting in a myeloid landscape that suppressed antitumor immunity.

Earthy and musty off-flavors are routinely observed in farmed trout worldwide. The microbial association to the production of those off-flavors was previously reported. The current manuscript aimed to catalog the microbial enrichment (eukaryotes and prokaryotes) in semi-intensive aquaculture freshwater sources that might influence the trout aquaculture quality production. The 16S rRNA and ITS metabarcoding analyses were applied on the inflow- and pond-water samples from trout farms previously recorded a malodor fish products and located alongside Moosach and Sempt Rivers in Bavaria province, Germany. The results showed that more than 99% of the detected prokaryotic OTUs (Operational Taxonomic Unit identification) were bacteria as of ~ 75.57% were Proteobacteria, and ~ 14.4% were Bacteroidetes. Meanwhile, 118 out of 233 of the eukaryotic OTUs were known species. Of these, ~ 45% were plant pathogens, and ~ 28% were mushroom/yeasts. Based on the comparative analysis between inflow- and pond-water samples, several pro- and eukaryotic microorganisms that affect the trout aquaculture water quality and industry have been detected, including the malodor-producing microorganisms, e.g., Cyanobacteria and Actinobacteria, along with fish infectious microorganisms, e.g., Chilodonella cyprinid, Metschnikowia bicuspidate. Additionally, the effect of the human- and industrial-related activities around the sampling area on the microbiota of the investigated farms were highlighted.

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