Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade.

The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function. SIGNIFICANCE: This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti-PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell-mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function. See related commentary by Lin et al., p. 2507. This article is featured in Selected Articles from This Issue, p. 2489.

Lateral hypothalamic leptin receptor neurons drive hunger-gated food-seeking and consummatory behaviours in male mice.

For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons are known to regulate motivated behaviours, yet which subpopulation drives food seeking and consummatory behaviours have not been fully addressed. Here, in male mice, fibre photometry recordings demonstrated that LH leptin receptor (LepR) neurons are correlated explicitly in both voluntary seeking and consummatory behaviours. Further, micro-endoscope recording of the LHLepR neurons demonstrated that one subpopulation is time-locked to seeking behaviours and the other subpopulation time-locked to consummatory behaviours. Seeking or consummatory phase specific paradigm revealed that activation of LHLepR neurons promotes seeking or consummatory behaviours and inhibition of LHLepR neurons reduces consummatory behaviours. The activity of LHLepR neurons was increased via Neuropeptide Y (NPY) which acted as a tonic permissive gate signal. Our results identify neural populations that mediate seeking and consummatory behaviours and may lead to therapeutic targets for maladaptive food seeking and consummatory behaviours.

Feasibility study on cross-linked biopolymeric concrete encapsulating selenium glass wastes.

Feasibility study was conducted to encapsulate the selenium (Se) contained in glass waste, using the biopolymer-modified concrete. Biopolymer has unique characteristics to provide the chemical sites to metals or toxic compounds through the three-dimensional cross-linked structure. Very minute amount of biopolymer enhanced the characteristics of cementitious material. The resulting biopolymeric composite with selenium glass waste showed 20% higher compressive strength than ordinary concrete and the lower leaching concentration than the equipment detection limit. For a qualitative measurement, X-ray diffraction (XRD; X-ray powder diffractogram) was used to characterize the biopolymeric concrete. The optimum waste content percentage with appropriate biopolymer concrete mixture ratio was identified for its possible commercial use.

Evaluation of pilot-scale in-vessel composting for food waste treatment.

This study is aimed to evaluate the performance of pilot-scale in-vessel composting for food wastes treatment. The composting plant was installed with 324 m3 of the composting bay volume and 14,000 kg/day of the composting material flow rate. The evaluations studied included the operational indices, the compost maturity indices, and the quality of the final compost. Blowers of this system were useful in maintaining aerobic condition (over 6% oxygen concentration in off-gas) through the entire compost bay. The levels of indices evaluated remained constant in the final part of composting. The final compost was satisfactory for its agricultural application. It was revealed in this study that bulk density bore a linear relation to moisture content during composting, and the final compost without bulking agent showed negative correlation between heavy metal and organic matters content.

Differential effect of phosphodiesterase IV inhibitor RP73401 on various inflammatory and immune responses relevent to rheumatoid arthritis.

Phosphodiesterase (PDE) IV inhibitors have been reported to possess potent anti-inflammatory activities through enhancement of cAMP. In this study, the immunopharmacological effect of PDE IV inhibitor (RP73401) was further carefully evaluated. RP73401 strongly blocked the production of tumor necrosis factor (TNF)-alpha from lipopolysaccharide (LPS)-stimulated murine macrophages (RAW264.7) and human peripheral blood mononuclear cells (PBMC) and LPS-primed mice. RP73401 did not relieve joint inflammation in adjuvant-arthritis (RA) model, whereas the compound attenuated arachidonic acid-induced inflammation. RP73401 displayed weak or no modulatory effects on the activation of macrophage and lymphocytes (assessed by proliferation, nitric oxide (NO) release and cell-cell adhesion, TNF-alpha production upon phorbol 12-myristate 13-acetate (PMA) treatment), and fluorescein-isothiocynate (FITC)-induced ear oedema. Collectively, these data suggest that PDE IV inhibitor RP73401 may differentially modulate various immune responses and these may explain its inability to inhibit adjuvant-induced joint inflammation or FITC-induced ear oedema.