bims-stacyt 2020-12-13 papers

Cell. 2020 Dec 07. pii: S0092-8674(20)31526-9. [Epub ahead of print]

Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.

Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8+ T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8+ T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8+ T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8+ T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8+ T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.

Keywords: CD8+ T cells; anti-tumor immunity; colorectal cancer; fat oxidation; metabolism; obesity; tumor microenvironment

DOI: https://doi.org/10.1016/j.cell.2020.11.009

Brain Behav Immun. 2020 Dec 08. pii: S0889-1591(20)32452-1. [Epub ahead of print]

The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice.

Maximilian Franke, Michael Bieber, Peter Kraft, Alexander N R Weber, Guido Stoll, Michael K Schuhmann.

PURPOSE: Cerebral ischemia induces a profound neuro-inflammatory response, but the underlying molecular mechanisms are poorly understood. Inflammasomes (NLRP1, NLRP3, NLRC4, AIM2) are intracellular multi-protein complexes which can induce sets of pro-inflammatory cyto- and chemokines, and thereby guide inflammation. We, here, assessed the functional role of NLRP3 in ischemia/reperfusion (I/R) injury in a mouse model of transient cerebral ischemia.
METHODS: Ischemic stroke was induced in C57Bl/6 mice by 60 minutes transient middle cerebral artery occlusion (tMCAO) and 3, 7 or 23 hours of reperfusion, a paradigm of I/R injury. The expression patterns of inflammasomes in the ischemic hemispheres were evaluated by semiquantitative real-time PCR and Western Blot analysis accompanied by protein localization using immunocytochemistry. Finally, animals were treated with the inflammasome inhibitors Sulforaphane, Genipin, MCC950 or vehicle, directly before or upon recanalization after tMCAO. Stroke outcome was assessed, including infarct size and functional deficits, local inflammatory response, neuronal survival as well as blood-brain barrier function on day 1 after tMCAO.
RESULTS: After tMCAO the relative gene expression levels of NLRP3 increased 20-30x within 1 day in the ischemic hemisphere which translated into an increased expression of NLRP3 in neurons. Accordingly, the gene expression levels of the NLRP3-modulator, Bruton's Tyrosine Kinase (BTK), and the NLRP3-inducible cytokine, IL-1β significantly rose. Lesser or non-significant changes were seen for the other inflammasomes. Application of inflammasome inhibitors covering all inflammasomes or specifically NLRP3 significantly reduced infarct volumes when given before or after tMCAO and was accompanied by clear evidence for reduced activation of caspase 1. This stroke attenuating effect coincided with less immune cell infiltration in the ischemic hemisphere and preservation of the blood-brain barrier integrity.
CONCLUSIONS: Our data show that induction of the NLRP3 inflammasome in neurons drives neuroinflammation in acute ischemic stroke. Early blockade of NLRP3 protects from I/R injury by mitigating inflammation and stabilizing the blood-brain barrier.

Keywords: AIM2; BTK; Blood-brain barrier; Inflammasome; Ischemia-reperfusion injury; Ischemic stroke; NLRC4; NLRP1; NLRP3; Thrombo-inflammation

DOI: https://doi.org/10.1016/j.bbi.2020.12.009

Med Res Rev. 2020 Dec 11.

The role of hypoxia-inducible factor 1 in tumor immune evasion.

Li You, Wenda Wu, Xu Wang, Liurong Fang, Vojtech Adam, Eugenie Nepovimova, Qinghua Wu, Kamil Kuca.

Hypoxia-inducible factor 1 (HIF-1) plays an indispensable role in the hypoxic tumor microenvironment. Hypoxia and HIF-1 are involved in multiple aspects of tumor progression, such as metastasis, angiogenesis, and immune evasion. In innate and adaptive immune systems, malignant tumor cells avoid their recognition and destruction by HIF-1. Tumor immune evasion allows cancer cells to proliferate and metastasize and is associated with immunotherapy failure and chemoresistance. In the hypoxic tumor microenvironment, HIF-1 signaling suppresses the innate and adaptive immune systems to evade immune attack by inducing the expression of immunosuppressive factors and immune checkpoint molecules, including vascular endothelial growth factor, prostaglandin E2 , and programmed death-ligand 1/programmed death-1. Moreover, HIF-1 blocks tumor-associated antigen presentation via major histocompatibility complex class I chain-related/natural killer group 2, member D signaling. Tumor-associated autophagy and the release of tumor-derived exosomes contribute to HIF-1-mediated immune evasion. This review focuses on recent findings on the potential mechanism(s) underlying the effect of hypoxia and HIF-1 signaling on tumor immune evasion in the hypoxic tumor microenvironment. The effects of HIF-1 on immune checkpoint molecules, immunosuppressive molecules, autophagy, and exosomes have been described. Additionally, the potential role of HIF-1 in the regulation of tumor-derived exosomes, as well as the roles of HIF-1 and exosomes in tumor evasion, are discussed. This study will contribute to our understanding of HIF-1-mediated tumor immune evasion, leading to the development of effective HIF-1-targeting drugs and immunotherapies.

Keywords: HIF-1; PD-L1; exosomes; hypoxia; tumor immune evasion

DOI: https://doi.org/10.1002/med.21771