bims-stacyt 2019-09-22 papers

Cells. 2019 Sep 14. pii: E1083. [Epub ahead of print]8(9):

Improving Cancer Immunotherapy by Targeting the Hypoxic Tumor Microenvironment: New Opportunities and Challenges.

Muhammad Zaeem Noman, Meriem Hasmim, Audrey Lequeux, Malina Xiao, Caroline Duhem, Salem Chouaib, Guy Berchem, Bassam Janji.

Initially believed to be a disease of deregulated cellular and genetic expression, cancer is now also considered a disease of the tumor microenvironment. Over the past two decades, significant and rapid progress has been made to understand the complexity of the tumor microenvironment and its contribution to shaping the response to various anti-cancer therapies, including immunotherapy. Nevertheless, it has become clear that the tumor microenvironment is one of the main hallmarks of cancer. Therefore, a major challenge is to identify key druggable factors and pathways in the tumor microenvironment that can be manipulated to improve the efficacy of current cancer therapies. Among the different tumor microenvironmental factors, this review will focus on hypoxia as a key process that evolved in the tumor microenvironment. We will briefly describe our current understanding of the molecular mechanisms by which hypoxia negatively affects tumor immunity and shapes the anti-tumor immune response. We believe that such understanding will provide insight into the therapeutic value of targeting hypoxia and assist in the design of innovative combination approaches to improve the efficacy of current cancer therapies, including immunotherapy.

Keywords: HIF; autophagy; hypoxia; immune checkpoints; immunotherapy; tumor microenvironment

DOI: https://doi.org/10.3390/cells8091083

Cell Stress. 2019 Jul 03. 3(9): 295-309

Immunosurveillance of cancer cell stress.

Seila Lorenzo-Herrero, Christian Sordo-Bahamonde, Segundo González, Alejandro López-Soto.

Cancer development is tightly controlled by effector immune responses that recognize and eliminate malignantly transformed cells. Nonetheless, certain immune subsets, such as tumor-associated macrophages, have been described to promote tumor growth, unraveling a double-edge role of the immune system in cancer. Cell stress can modulate the crosstalk between immune cells and tumor cells, reshaping tumor immunogenicity and/or immune function and phenotype. Infiltrating immune cells are exposed to the challenging conditions typically present in the tumor microenvironment. In return, the myriad of signaling pathways activated in response to stress conditions may tip the balance toward stimulation of antitumor responses or immune-mediated tumor progression. Here, we explore how distinct situations of cellular stress influence innate and adaptive immunity and the consequent impact on cancer establishment and progression.

Keywords: cancer; cell stress; immune system; immunosurveillance; tumor immunity

DOI: https://doi.org/10.15698/cst2019.09.198

J Cancer. 2019 ;10(19): 4574-4587

Cellular Interactions in the Tumor Microenvironment: The Role of Secretome.

Bianca Rodrigues da Cunha, Célia Domingos, Ana Carolina Buzzo Stefanini, Tiago Henrique, Giovana Mussi Polachini, Pedro Castelo-Branco, Eloiza Helena Tajara.

Over the past years, it has become evident that cancer initiation and progression depends on several components of the tumor microenvironment, including inflammatory and immune cells, fibroblasts, endothelial cells, adipocytes, and extracellular matrix. These components of the tumor microenvironment and the neoplastic cells interact with each other providing pro and antitumor signals. The tumor-stroma communication occurs directly between cells or via a variety of molecules secreted, such as growth factors, cytokines, chemokines and microRNAs. This secretome, which derives not only from tumor cells but also from cancer-associated stromal cells, is an important source of key regulators of the tumorigenic process. Their screening and characterization could provide useful biomarkers to improve cancer diagnosis, prognosis, and monitoring of treatment responses.

Keywords: Cancer; Microenvironment; Secretome.

DOI: https://doi.org/10.7150/jca.21780

Cell Metab. 2019 Sep 09. pii: S1550-4131(19)30448-6. [Epub ahead of print]

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions.

Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.

Keywords: FGF21; de novo serine biosynthesis; endocrine signaling; mitochondrial disease; mitochondrial integrated stress response; mitochondrial unfolded protein response; one carbon cycle; stress response

DOI: https://doi.org/10.1016/j.cmet.2019.08.019