bims-stacyt 2020-11-01 papers

Cancer Immunol Immunother. 2020 Oct 26.

Stress relief for cancer immunotherapy: implications for the ER stress response in tumor immunity.

Alex M Andrews, Megan D Tennant, Jessica E Thaxton.

The solid tumor microenvironment is replete with factors that present a stress to infiltrating immune cells. Endoplasmic reticulum (ER) stress sensor PKR-like ER kinase (PERK) is primed to sense and respond to the burden of misfolded proteins in the ER lumen induced by cell stressors. PERK has documented roles as a master regulator of acute and chronic responses to cell stress as well as in the regulation of cell metabolism. Here, we provide an overview of the roles of PERK based on what is known and remains to be tested in immune cells in tumors and impacts on tumor control. PERK is one of several ER kinases able to preferentially induce activating transcription factor 4 (ATF4) as a response to cell stress. ATF4 orchestrates the oxidative stress response and governs amino acid metabolism. We discuss the tested role of ATF4 in tumor immunity and provide insight on the dueling protective and deleterious roles that ATF4 may play in the stress of solid tumors.

Keywords: ATF4; Cancer immunotherapy; ER stress; Metabolism; PERK; T cell; Translation

DOI: https://doi.org/10.1007/s00262-020-02740-3

Front Cell Dev Biol. 2020 ;8 846

Transmissible Endoplasmic Reticulum Stress: A Novel Perspective on Tumor Immunity.

Zhou Jiang, Geru Zhang, Liwei Huang, Yihang Yuan, Chenzhou Wu, Yi Li.

As the first compartment of the protein secretory pathway, the endoplasmic reticulum (ER) acts as a protein synthesis factory, maintaining proteostasis and ER homeostasis. However, a variety of intrinsic and extrinsic perturbations, such as cancer, can disrupt the homeostasis and result in a large accumulation of misfolded/unfolded proteins in the ER lumen, thereby provoking a specific cellular state addressed as "ER stress". Then the unfolded protein response (UPR), an adaptive signaling pathway, is triggered to address the stress and restore the homeostasis. A novel aspect of ER stress is that it can be transmitted from cancer cells to tumor-infiltrating myeloid cells through certain cancer cell-released soluble factors, which is termed as transmissible ER stress (TERS) or ER stress resonance (ERSR). In this review, we provide a comprehensive overview of the link between cancer and ER stress as well as the possible soluble factors mediating TERS. We further elaborate the cell-extrinsic effects of TERS on tumor immunity, and how it indirectly modulates cancer development and progression, which is expected to add a new dimension to anticancer therapy.

Keywords: cancer; transmissible ER stress; tumor immunity; tumor-derived extracellular vesicles; unfolded protein response

DOI: https://doi.org/10.3389/fcell.2020.00846

Cancer Cell. 2020 Sep 23. pii: S1535-6108(20)30478-5. [Epub ahead of print]

Immunometabolic Interplay in the Tumor Microenvironment.

Irem Kaymak, Kelsey S Williams, Jason R Cantor, Russell G Jones.

Immune cells' metabolism influences their differentiation and function. Given that a complex interplay of environmental factors within the tumor microenvironment (TME) can have a profound impact on the metabolic activities of immune, stromal, and tumor cell types, there is emerging interest to advance understanding of these diverse metabolic phenotypes in the TME. Here, we discuss cell-extrinsic contributions to the metabolic activities of immune cells. Then, considering recent technical advances in experimental systems and metabolic profiling technologies, we propose future directions to better understand how immune cells meet their metabolic demands in the TME, which can be leveraged for therapeutic benefit.

Keywords: immunology; immunometabolism; in vitro modeling; metabolism; metabolomics; physiologic media; stable isotope tracing; tumor microenvironment

DOI: https://doi.org/10.1016/j.ccell.2020.09.004