bims-stacyt 2020-09-13 papers

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2020–09–13
two papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Metabolic regulation of immune cells in proinflammatory microenvironments and diseases during ageing.
Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer.

Ageing Res Rev. 2020 Sep 05. pii: S1568-1637(20)30300-7. [Epub ahead of print] 101165

Metabolic regulation of immune cells in proinflammatory microenvironments and diseases during ageing.

Pei-Heng Li, Ran Zhang, Li-Qin Cheng, Jin-Jing Liu, Hou-Zao Chen.

  The process of ageing includes molecular changes within cells and interactions between cells, eventually resulting in age-related diseases. Although various cells (immune cells, parenchymal cells, fibroblasts and endothelial cells) in tissues secrete proinflammatory signals in age-related diseases, immune cells are the major contributors to inflammation. Many studies have emphasized the role of metabolic dysregulation in parenchymal cells in age-related inflammatory diseases. However, few studies have discussed metabolic modifications in immune cells during ageing. In this review, we introduce the metabolic dysregulation of major nutrients (glucose, lipids, and amino acids) within immune cells during ageing, which leads to dysfunctional NAD + metabolism that increases immune cell senescence and leads to the acquisition of the corresponding senescence-associated secretory phenotype (SASP). We then focus on senescent immune cell interactions with parenchymal cells and the extracellular matrix and their involvement in angiogenesis, which lead to proinflammatory microenvironments in tissues and inflammatory diseases at the systemic level. Elucidating the roles of metabolic modifications in immune cells during ageing will provide new insights into the mechanisms of ageing and therapeutic directions for age-related inflammatory diseases.

Keywords:  ageing; immune cell; inflammatory disease; metabolism; senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1016/j.arr.2020.101165
Cancer Immunol Res. 2020 Sep 11. pii: canimm.0111.2020. [Epub ahead of print]

Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer.

Xuguang Yang, Yun Lu, Junjie Hang, Junfeng Zhang, Tiening Zhang, Yanmiao Huo, Jun Liu, Songtao Lai, Dawei Luo, Liwei Wang, Rong Hua, Yuli Lin.

The mechanisms responsible for radioresistance in pancreatic cancer have yet to be elucidated and the suppressive tumor immune microenvironment must be considered. We investigated if the radiotherapy-augmented Warburg effect helped myeloid cells acquire an immunosuppressive phenotype, resulting in limited treatment efficacy of pancreatic ductal adenocarcinoma (PDAC). Radiotherapy enhanced the tumor-promoting activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer. Sustained increase in lactate secretion, resulting from the radiation-augmented Warburg effect, was responsible for the enhanced immunosuppressive phenotype of MDSCs after radiotherapy. Hypoxia-inducible factor-1α (HIF-1α) was essential for tumor cell metabolism and lactate-regulated activation of MDSCs via the G protein-coupled receptor 81 (GPR81)/ mammalian target of rapamycin (mTOR)/HIF-1α/STAT3 pathway. Blocking lactate production in tumor cells or deleting Hif-1α in MDSCs reverted antitumor T cell responses and effectively inhibited tumor progression after radiotherapy in pancreatic cancer. Our investigation highlighted the importance of radiation-induced lactate in regulating the inhibitory immune microenvironment of PDAC. Targeting lactate derived from tumor cells and the HIF-1α signaling in MDSCs may hold distinct promise for clinical therapies to alleviate radioresistance in PDAC.

DOI: https://doi.org/10.1158/2326-6066.CIR-20-0111