bims-stacyt 2019-05-05 papers

Cell. 2019 Apr 19. pii: S0092-8674(19)30280-6. [Epub ahead of print]

Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR.

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

Keywords: IL-23; UPR; dendritic cells; fatty acids; glycolysis; hexokinase; innate immunity; metabolic reprogramming; mtROS; psoriasis

DOI: https://doi.org/10.1016/j.cell.2019.03.018

Sci Immunol. 2019 May 03. pii: eaax0416. [Epub ahead of print]4(35):

Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33.

T Mahlakõiv, A-L Flamar, L K Johnston, S Moriyama, G G Putzel, P J Bryce, D Artis.

Obesity is driven by chronic low-grade inflammation resulting from dysregulated immune cell accumulation and function in white adipose tissue (WAT). Interleukin-33 (IL-33) is a key cytokine that controls innate and adaptive immune cell activity and immune homeostasis in WAT, although the sources of IL-33 have remained controversial. Here, we show that WAT-resident mesenchyme-derived stromal cells are the dominant producers of IL-33. Adipose stem and progenitor cells (ASPCs) produced IL-33 in all WAT depots, whereas mesothelial cells served as an additional source of IL-33 in visceral WAT. ASPC-derived IL-33 promoted a regulatory circuit that maintained an immune tone in WAT via the induction of group 2 innate lymphoid cell-derived type 2 cytokines and maintenance of eosinophils, whereas mesothelial IL-33 also acted as an alarmin by inducing peritoneal immune response upon infection. Together, these data reveal a previously unrecognized regulatory network between tissue-resident progenitor cells and innate lymphoid cells that maintains immune homeostasis in adipose tissue.

DOI: https://doi.org/10.1126/sciimmunol.aax0416

Cell Metab. 2019 Apr 18. pii: S1550-4131(19)30186-X. [Epub ahead of print]

Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment.

Xingzhe Ma, Enguang Bi, Yong Lu, Pan Su, Chunjian Huang, Lintao Liu, Qiang Wang, Maojie Yang, Matthew F Kalady, Jianfei Qian, Aijun Zhang, Anisha A Gupte, Dale J Hamilton, Chengyun Zheng, Qing Yi.

Tumor-infiltrating T cells often lose their effector function; however, the mechanisms are incompletely understood. We report that cholesterol in the tumor microenvironment induces CD8+ T cell expression of immune checkpoints and exhaustion. Tumor tissues enriched with cholesterol and cholesterol content in tumor-infiltrating CD8+ T cells were positively and progressively associated with upregulated T cell expression of PD-1, 2B4, TIM-3, and LAG-3. Adoptively transferred CD8+ T cells acquired cholesterol, expressed high levels of immune checkpoints, and became exhausted upon entering a tumor. Tumor culture supernatant or cholesterol induced immune checkpoint expression by increasing endoplasmic reticulum (ER) stress in CD8+ T cells. Consequently, the ER stress sensor XBP1 was activated and regulated PD-1 and 2B4 transcription. Inhibiting XBP1 or reducing cholesterol in CD8+ T cells effectively restored antitumor activity. This study reveals a mechanism underlying T cell exhaustion and suggests a new strategy for restoring T cell function by reducing cholesterol to enhance T cell-based immunotherapy.

Keywords: CD8+ T cells; cholesterol; exhaustion; immune checkpoints; tumor microenvironment

DOI: https://doi.org/10.1016/j.cmet.2019.04.002

Front Immunol. 2019 ;10 757

Tumor-Stroma-Inflammation Networks Promote Pro-metastatic Chemokines and Aggressiveness Characteristics in Triple-Negative Breast Cancer.

Yulia Liubomirski, Shalom Lerrer, Tsipi Meshel, Linor Rubinstein-Achiasaf, Dina Morein, Stefan Wiemann, Cindy Körner, Adit Ben-Baruch.

The tumor microenvironment (TME) plays key roles in promoting disease progression in the aggressive triple-negative subtype of breast cancer (TNBC; Basal/Basal-like). Here, we took an integrative approach and determined the impact of tumor-stroma-inflammation networks on pro-metastatic phenotypes in TNBC. With the TCGA dataset we found that the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β), as well as their target pro-metastatic chemokines CXCL8 (IL-8), CCL2 (MCP-1), and CCL5 (RANTES) were expressed at significantly higher levels in basal patients than luminal-A patients. Then, we found that TNFα- or IL-1β-stimulated co-cultures of TNBC cells (MDA-MB-231, MDA-MB-468, BT-549) with mesenchymal stem cells (MSCs) expressed significantly higher levels of CXCL8 compared to non-stimulated co-cultures or each cell type alone, with or without cytokine stimulation. CXCL8 was also up-regulated in TNBC co-cultures with breast cancer-associated fibroblasts (CAFs) derived from patients. CCL2 and CCL5 also reached the highest expression levels in TNFα/IL-1β-stimulated TNBC:MSC/CAF co-cultures. The elevations in CXCL8 and CCL2 expression partly depended on direct physical contacts between the tumor cells and the MSCs/CAFs, whereas CCL5 up-regulation was entirely dependent on cell-to-cell contacts. Supernatants of TNFα-stimulated TNBC:MSC "Contact" co-cultures induced robust endothelial cell migration and sprouting. TNBC cells co-cultured with MSCs and TNFα gained migration-related morphology and potent migratory properties; they also became more invasive when co-cultured with MSCs/CAFs in the presence of TNFα. Using siRNA to CXCL8, we found that CXCL8 was significantly involved in mediating the pro-metastatic activities gained by TNFα-stimulated TNBC:MSC "Contact" co-cultures: angiogenesis, migration-related morphology of the tumor cells, as well as cancer cell migration and invasion. Importantly, TNFα stimulation of TNBC:MSC "Contact" co-cultures in vitro has increased the aggressiveness of the tumor cells in vivo, leading to higher incidence of mice with lung metastases than non-stimulated TNBC:MSC co-cultures. Similar tumor-stromal-inflammation networks established in-culture with luminal-A cells demonstrated less effective or differently-active pro-metastatic functions than those of TNBC cells. Overall, our studies identify novel tumor-stroma-inflammation networks that may promote TNBC aggressiveness by increasing the pro-malignancy potential of the TME and of the tumor cells themselves, and reveal key roles for CXCL8 in mediating these metastasis-promoting activities.

Keywords: CCL2; CCL5; CXCL8; cancer-associated fibroblasts; interleukin 1β; mesenchymal stem cells; triple-negative breast cancer; tumor necrosis factor α

DOI: https://doi.org/10.3389/fimmu.2019.00757

Mol Carcinog. 2019 Apr 30.

The multiple roles of the unfolded protein response regulator IRE1α in cancer.

Fiona Chalmers, Saie Mogre, Jeongin Son, Nicholas Blazanin, Adam B Glick.

Cancer is associated with a number of conditions such as hypoxia, nutrient deprivation, cellular redox, and pH changes that result in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) and trigger a stress response known as the unfolded protein response (UPR). The UPR is a conserved cellular survival mechanism mediated by the ER transmembrane proteins activating transcription factor 6, protein kinase-like endoplasmic reticulum kinase, and inositol-requiring enzyme 1α (IRE1α) that act to resolve ER stress and promote cell survival. IRE1α is a kinase/endoribonuclease (RNase) with multiple activities including unconventional splicing of the messenger RNA (mRNA) for the transcription factor X-Box Binding Protein 1 (XBP1), degradation of other mRNAs in a process called regulated IRE1α-dependent decay (RIDD) and activation of a pathway leading to c-Jun N-terminal kinase phosphorylation. Each of these outputs plays a role in the adaptive and cell death responses to ER stress. Many studies indicate an important role for XBP1 and RIDD functions in cancer and new studies suggest that these two functions of the IRE1α RNase can have opposing functions in the early and later stages of cancer pathogenesis. Finally, as more is learned about the context-dependent role of IRE1α in cancer development, specific small molecule inhibitors and activators of IRE1α could play an important role in counteracting the protective shield provided by ER stress signaling in cancer cells.

Keywords: X-Box Binding Protein 1; endoplasmic reticulum stress; inositol-requiring enzyme 1α; regulated IRE1α-dependent decay; unfolded protein response

DOI: https://doi.org/10.1002/mc.23031

Nat Metab. 2019 Jan;1 16-33

Coupling Krebs cycle metabolites to signalling in immunity and cancer.

Dylan G Ryan, Michael P Murphy, Christian Frezza, Hiran A Prag, Edward T Chouchani, Luke A O'Neill, Evanna L Mills.

Metabolic reprogramming has become a key focus for both immunologists and cancer biologists, with exciting advances providing new insights into underlying mechanisms of disease. Metabolites traditionally associated with bioenergetics or biosynthesis have been implicated in immunity and malignancy in transformed cells, with a particular focus on intermediates of the mitochondrial pathway known as the Krebs cycle. Among these, the intermediates succinate, fumarate, itaconate, 2-hydroxyglutarate isomers (D-2-hydroxyglutarate and L-2-hydroxyglutarate) and acetyl-CoA now have extensive evidence for "non-metabolic" signalling functions in both physiological immune contexts and in disease contexts, such as the initiation of carcinogenesis. This review will describe how metabolic reprogramming, with emphasis placed on these metabolites, leads to altered immune cell and transformed cell function. The latest findings are informative for new therapeutic approaches which could be transformative for a range of diseases.

DOI: https://doi.org/10.1038/s42255-018-0014-7