bims-stacyt 2022-05-08 papers

Inflamm Regen. 2022 May 01. 42(1): 13

Molecular mechanism of crosstalk between immune and metabolic systems in metabolic syndrome.

Rumi Hachiya, Miyako Tanaka, Michiko Itoh, Takayoshi Suganami.

Chronic inflammation is currently considered as a molecular basis of metabolic syndrome. Particularly, obesity-induced inflammation in adipose tissue is the origin of chronic inflammation of metabolic syndrome. Adipose tissue contains not only mature adipocytes with large lipid droplets, but also a variety of stromal cells including adipocyte precursors, vascular component cells, immune cells, and fibroblasts. However, crosstalk between those various cell types in adipose tissue in obesity still remains to be fully understood. We focus on two innate immune receptors, Toll-like receptor 4 (TLR4) and macrophage-inducible C-type lectin (Mincle). We provided evidence that adipocyte-derived saturated fatty acids (SFAs) activate macrophage TLR4 signaling pathway, thereby forming a vicious cycle of inflammatory responses during the development of obesity. Intriguingly, the TLR4 signaling pathway is modulated metabolically and epigenetically: SFAs augment TLR4 signaling through the integrated stress response and chromatin remodeling, such as histone methylation, regulates dynamic transcription patterns downstream of TLR4 signaling. Another innate immune receptor Mincle senses cell death, which is a trigger of chronic inflammatory diseases including obesity. Macrophages form a histological structure termed "crown-like structure (CLS)", in which macrophages surround dead adipocytes to engulf cell debris and residual lipids. Mincle is exclusively expressed in macrophages forming the CLS in obese adipose tissue and regulates adipocyte death-triggered adipose tissue fibrosis. In addition to adipose tissue, we found a structure similar to CLS in the liver of nonalcoholic steatohepatitis (NASH) and the kidney after acute kidney injury. This review article highlights the recent progress of the crosstalk between immune and metabolic systems in metabolic syndrome, with a focus on innate immune receptors.

Keywords: Crown-like structure; Fatty acids; Metabolic syndrome; Mincle; Obesity; TLR4

DOI: https://doi.org/10.1186/s41232-022-00198-7

Curr Res Immunol. 2021 ;2 132-141

Tumor-infiltrating T-regulatory cells adapt to altered metabolism to promote tumor-immune escape.

Tania Sarkar, Subhanki Dhar, Gaurisankar Sa.

Tumor mass and its microenvironment alter host immune system in various ways to promote tumor growth. One of the modifications is evasion of immune surveillance by augmenting the number of Tregs in tumor vicinity. Elevated levels of Tregs are seen in peripheral circulation and tumor tissue of cancer patients. Cancer cells release several chemokines to attract Tregs in tumor-site. Infiltration of Tregs has clinical significance because being immunosuppressive infiltrating Tregs suppress other immune cells making the tumor microenvironment favorable for tumor growth. On the other hand, infiltrating Tregs show metabolic alteration in tumor microenvironment which allows their selective survival over the others. Persistence of Tregs in the tumor microenvironment and subsequent immunosuppression makes Tregs a potential therapeutic obstacle and the reason behind the failure of immunotherapy. In this review, we emphasize the recent development in the metabolic adaptation of tumor-infiltrating Tregs and the therapeutic approaches to boost immunity against cancer.

Keywords: Anti-Tumor immunity; CCL/CXCL, Chemokine ligand; CCR/CXCR, Chemokine receptor; FOXP3, Forkhead box P3; IL, Interleukin; Immune-suppression; Metabolism; NK cell, Natural killer cell; T-regulatory cell; TGFβ, Transforming growth factor-beta; TME, Tumor microenvironment; Treg, T-regulatory cell; Tumor microenvironment

DOI: https://doi.org/10.1016/j.crimmu.2021.08.002

Cancer Discov. 2022 May 06. OF1

RIPK1 Promotes Intrinsic and Extrinsic Resistance to Immunotherapy.

RIPK1 loss enhances immunotherapy by reshaping immune populations and poising tumor cells for killing.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-077

J Clin Invest. 2022 May 02. pii: e156774. [Epub ahead of print]132(9):

HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy.

Shaima Salman, David J Meyers, Elizabeth E Wicks, Sophia N Lee, Emmanuel Datan, Aline M Thomas, Nicole M Anders, Yousang Hwang, Yajing Lyu, Yongkang Yang, Walter Jackson, Dominic Dordai, Michelle A Rudek, Gregg L Semenza.

Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and available therapies, including immunotherapies, are ineffective for many patients. HCC is characterized by intratumoral hypoxia, and increased expression of hypoxia-inducible factor 1α (HIF-1α) in diagnostic biopsies is associated with patient mortality. Here we report the development of 32-134D, a low-molecular-weight compound that effectively inhibits gene expression mediated by HIF-1 and HIF-2 in HCC cells, and blocks human and mouse HCC tumor growth. In immunocompetent mice bearing Hepa1-6 HCC tumors, addition of 32-134D to anti-PD1 therapy increased the rate of tumor eradication from 25% to 67%. Treated mice showed no changes in appearance, behavior, body weight, hemoglobin, or hematocrit. Compound 32-134D altered the expression of a large battery of genes encoding proteins that mediate angiogenesis, glycolytic metabolism, and responses to innate and adaptive immunity. This altered gene expression led to significant changes in the tumor immune microenvironment, including a decreased percentage of tumor-associated macrophages and myeloid-derived suppressor cells, which mediate immune evasion, and an increased percentage of CD8+ T cells and natural killer cells, which mediate antitumor immunity. Taken together, these preclinical findings suggest that combining 32-134D with immune checkpoint blockade may represent a breakthrough therapy for HCC.

Keywords: Cancer immunotherapy; Liver cancer; Oncology; Therapeutics; Transcription

DOI: https://doi.org/10.1172/JCI156774

Cell Metab. 2022 Apr 23. pii: S1550-4131(22)00130-9. [Epub ahead of print]

Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer.

Sarah A Best, Patrick M Gubser, Shalini Sethumadhavan, Ariena Kersbergen, Yashira L Negrón Abril, Joshua Goldford, Katherine Sellers, Waruni Abeysekera, Alexandra L Garnham, Jackson A McDonald, Clare E Weeden, Dovile Anderson, David Pirman, Thomas P Roddy, Darren J Creek, Axel Kallies, Gillian Kingsbury, Kate D Sutherland.

The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.

Keywords: KEAP1; KRAS; STK11/Lkb1; glutaminase; glutamine; immune microenvironment; immunotherapy; lung adenocarcinoma; metabolism

DOI: https://doi.org/10.1016/j.cmet.2022.04.003