Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation.

As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8+ T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.

Reconstituted CD74+ NK cells trigger chronic graft versus host disease after allogeneic bone marrow transplantation.

Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74- NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.

Synthesis of 2,3-Benzobicyclo[3.3.1]non-2-enes via a Cascade of Domino Carbocation Migration/Interrupted Ritter Reaction and Dienone-Phenol Rearrangement.

The 2,3-benzobicyclo[3.3.1]non-2-ene scaffold is a bridged backbone of many bioactive natural products. The development of a concise tactic toward this architecture is of keen interest and highly challenging. Herein, we disclose a novel cascade protocol for realizing this target. This approach relies on a domino sequence of carbocation rearrangement and Ritter reaction of the taiwaniaquinoid scaffold derivatives. A process of dienone-phenol rearrangement was postulated to be involved. Several potentially useful compounds with this intricate bridged ring were obtained in good overall yields (59-83%, over 2 steps).

Oxidative Dehydroxycyclization of Catechols with o-Mercaptoanilines to Access 1-Hydroxyphenothiazines.

The protocol of aerobic oxidative dehydroxycyclization installed in the synthesis of rarely studied 1-hydroxyphenothiazines from catechols and o-mercaptoanilines is presented. Utilizing a natural renewable low-toxicity gallic acid as an organocatalyst, this established transformation proceeded smoothly in an aqueous ethanol solution under mild conditions with good functional group compatibility and up to a 94% isolated yield. This protocol is also characterized by its operational simple workup involving only recrystallization, revealing its sustainability and synthetic practicability.

Total Synthesis of Ophiorrhine†A, G and Ophiorrhiside†E Featuring a Bioinspired Intramolecular Diels-Alder Cycloaddition.

We report the first total synthesis of the monoterpene indole alkaloids ophiorrhine A via a late stage bioinspired intramolecular Diels-Alder cycloaddition to form the intricate bridged and spirannic polycyclic system. Several strategies were investigated to construct the indolopyridone moiety of ophiorrhiside E, the postulated biosynthetic precursor of ophiorrhine A. Eventually, the Friedel-Crafts-type coupling of N-methyl indolyl-acetamide with a secologanin-derived acid chloride delivered ophiorrhine G. Cyclodehydration of a protected form of the latter was followed by the desired spontaneous intramolecular Diels-Alder cycloaddition of protected ophiorrhiside E leading to ophiorrhine A.

Bioinspired Divergent Oxidative Cyclization from Strictosidine and Vincoside Derivatives: Second-Generation Total Synthesis of (-)-Cymoside and Access to an Original Hexacyclic-Fused Furo[3,2-b]indoline.

The second-generation synthesis of (-)-cymoside as well as the formation of a new hexacyclic-fused furo[3,2-b]indoline framework is reported. After a Pictet-Spengler condensation between secologanin tetraacetate and tryptamine, the course of the cyclization of the 7-hydroxyindolenine intermediate, generated by oxidation with an oxaziridine, depended on the stereochemistry of the 3-position. The 3-(S)-strictosidine stereochemistry delivered efficiently the scaffold of cymoside via intramolecular coupling with the C16-C17 enol ether, while the 3-(R)-vincoside stereochemistry directed towards the reaction with the C18-C19 terminal alkene and the formation of the unexpected caged compound.

Enantioselective Total Synthesis of Cymoside through a Bioinspired Oxidative Cyclization of a Strictosidine Derivative.

The first total synthesis of the caged monoterpene indole alkaloid cymoside is reported. This natural product displays a unique hexacyclic-fused skeleton whose biosynthesis implies an early oxidative cyclization of strictosidine. Our approach to the furo[3,2-b]indoline framework relied on an unprecedented biomimetic sequence which started by the diastereoselective oxidation of the indole ring into a hydroxyindolenine which triggered the addition of an enol ether and was followed by the trapping of an oxocarbenium intermediate.

Electrochemical Dearomative 2,3-Difunctionalization of Indoles.

We report the use of electrochemistry to perform a direct oxidative dearomatization of indoles leading to 2,3-dialkoxy or 2,3-diazido indolines under undivided conditions at a constant current. This operationally simple electro-oxidative procedure avoids the use of an external oxidant and displays excellent functional group compatibility. The formation of the two C-O or C-N bonds is believed to arise from the oxidation of the indoles into radical cation intermediates.

Facile and scalable synthesis of baphicacanthin A by a two-pot procedure.

Facile two-pot total synthesis of baphicacanthin A, a natural phenoxazinone alkaloid isolated from the roots of Baphicacanthus cusia which has been utilized as a traditional chinese medicine to effectively treat disease caused by coronavirus, has been developed from simple and commercially available starting materials. Catalytic aerobic oxidative cross-cyclocondensation of equimolar 2-aminophenol and 3-methoxy-2-hydroxylphenol in water was used to construct the key molecular skeleton 2-hydroxy-3H-phenoxazin-3-one. Gram scale synthesis was realized in 80% overall yield with practical convenience.

Pictet-Spengler Reaction for the Chemical Synthesis of Strictosidine.

Strictosidine is the common biosynthetic precursor of Monoterpene Indole Alkaloids (MIA). A practical single-step procedure to assemble strictosidine from secologanin is described via a bioinspired Pictet-Spengler reaction. Mild conditions and purification by crystallization and flash chromatography allow access to the targeted product in fair yield.

Rapamycin Pretreatment Rescues the Bone Marrow AML Cell Elimination Capacity of CAR-T Cells.

PURPOSE: Ongoing clinical trials show limited efficacy for Chimeric antigen receptor (CAR) T treatment for acute myeloid leukemia (AML). The aim of this study was to identify potential causes of the reported limited efficacy from CAR-T therapies against AML. EXPERIMENTAL DESIGN: We generated CAR-T cells targeting Epithelial cell adhesion molecule (EpCAM) and evaluated their killing activity against AML cells. We examined the impacts of modulating mTORC1 and mTORC2 signaling in CAR-T cells in terms of CXCR4 levels. We examined the effects of a rapamycin pretreatment of EpCAM CAR-T cells (during ex vivo expansion) and assessed the in vivo antitumor efficacy of rapamycin-pretreated EpCAM CAR-T cells (including CXCR4 knockdown cells) and CD33 CAR-T cells in leukemia xenograft mouse models. RESULTS: EpCAM CAR-T exhibited killing activity against AML cells but failed to eliminate AML cells in bone marrow. Subsequent investigations revealed that aberrantly activated mTORC1 signaling in CAR-T cells results in decreased bone marrow infiltration and decreased the levels of the rapamycin target CXCR4. Attenuating mTORC1 activity with the rapamycin pretreatment increased the capacity of CAR-T cells to infiltrate bone marrow and enhanced the extent of bone marrow AML cell elimination in leukemia xenograft mouse models. CXCR4 knockdown experiments showed that CXCR4 contributes to the enhanced bone marrow infiltration capacity of EpCAM CAR-T cells and the observed reduction in bone marrow AML cells. CONCLUSIONS: Our study reveals a potential cause for the limited efficacy of CAR-T reported from current AML clinical trials and illustrates an easy-to-implement pretreatment strategy, which enhances the anti-AML efficacy of CAR-T cells.See related commentary by Maiti and Daver, p. 5739.