Tumor stress inside out: cell-extrinsic effects of the unfolded protein response in tumor cells modulate the immunological landscape of the tumor microenvironment.
The unfolded protein response (UPR) is a eukaryotic cellular adaptive mechanism that functions to cope with stress of the endoplasmic reticulum (ER). Accumulating evidence demonstrates that the tumor microenvironment contains stressors that elicit a UPR, which has been demonstrated to be a cell-intrinsic mechanism crucial for tumorigenesis. In addition, the UPR is a source of proinflammatory signaling whose downstream mediators may hamper antitumor immunity. We discuss how the UPR may impair Ag presentation, which could result in defective T cell priming, also leading to tumor escape and growth. Further, we discuss the recent finding that ER stress and attendant proinflammation can be transmitted from ER-stressed tumor cells to myeloid cells. The ideas presented suggest that, in addition to being a cell-intrinsic mechanism of tumor survival, the tumor UPR can serve as a cell-extrinsic regulator of tumorigenesis by remodeling the immune response in the tumor microenvironment.
Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Navin R
NR
Mahadevan
Maurizio
M
Zanetti
D000818:Animals; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D005057:Eukaryotic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*; D056811:Unfolded Protein Response / Q000235:genetics / Q000276:immunology*