Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.

Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.

A Protocol for the Ortho-Deuteration of Acidic Aromatic Compounds in D2O Catalyzed by Cationic RhIII.

Methods to catalytically introduce deuterium in synthetically useful yields ortho to a carboxylic acid directing group on arenes typically requires D2 or high catalyst loadings, which makes using these approaches cost prohibitive for large-scale synthesis (equipment and reagent costs respectively). Herein, we present a simplified approach using low catalyst loadings of cationic RhIII and D2O as both deuterium source and solvent and show its application to H/D exchange on various carboxylic acid substrates.

α-Radiolysis of ionic liquid irradiated with helium ion beam and the influence of radiolytic products on Dy3+ extraction.

Helium ion (He(+)) beam produced by a heavy ion linear accelerator was used to simulate α-rays for studying the radiation effect on 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid ([C4mim][NTf2]). The water-soluble radiolytic products of [C4mim][NTf2] under He(+) beam irradiation were analysed, and it was found that they were similar to those by γ-ray irradiation, but their amount was much less than that by γ-ray irradiation, which was attributed to the recombination of [C4mim][NTf2] radical cations in track by high linear energy transfer (LET) radiations of the He(+) beam. The extracting behaviour of Dy(3+) using irradiated [C4mim][NTf2] in combination with alkylated bis-triazinyl-pyridine (CA-BTP) was assessed, and found that the influence of He(+) beam on the extraction was less than that of γ-ray irradiation. In addition, radiolytic products have a different influence on Dy(3+) extraction at different doses; Dy(3+) partitioning decreases at 50 kGy due to the protonation of CA-BTP and the inhibition of cation exchange mechanism by radiation-formed hydrogen ions. The abnormal increase of Dy(3+) partitioning at 100 kGy is mainly attributed to the precipitation formed between Dy(3+) and radiolytic products (F(-) and SO3(2-)).