Anatomy of the cell extrinsic effects of endoplasmic reticulum stress in tumor facilitation

The tumor microenvironment is harbor to a variety of insults that privilege tumor cells to co-opt host immunity. Many of these insults, including nutrient deprivation and hypoxia, create endoplasmic reticulum (ER) stress for resident tumor cells. Emerging reports also suggest that ER stress in infiltrating myeloid cells leads to the immune dysfunction, rendering these inept in the eliminating the tumor and instead facilitative of tumor growth. We previously reported that this polarization may be mediated by factors derived from tumor cells undergoing ER stress that target immune infiltrating cells to then similarly undergo ER stress, termed transmissible ER stress (TERS).This dissertation advances the findings of TERS through three central aims. In Chapter 2, I probe the role of TERS on cancer cells using a prostate cancer cell model. My findings reveal that TERS experienced cancer cells gain cytoprotection over tumor microenvironmental challenges as well as chemotherapies, which was centrally mediated by the PERK arm of the UPR. Chapter 3 reports that myeloid cells infiltrating the tumor microenvironment undergo a polarization consistent with those affected by TERS. Chemical inhibition of IRE1α during TERS led to dramatic reduction in TERS driven inflammation, immune-suppression, and angiogenesis. Finally, Chapter 4 elucidates the identity of the molecules responsible for TERS. I found TERS activity is assignable to lipid soluble molecules. Lipidomic analysis identified TERS contained enriched eicosanoids, which could not cause ER stress but drive immune suppressive features. The ER stress inducing factor behind TERS is a novel mono-unsaturated fatty acid that caused increases in ER stress, pro-inflammation, and angiogenesis in myeloid cells as well as drove the surface expression of CD86 and PD-L1. These lines provide the elucidation of the novel factors tumor cells undergoing ER stress secrete to promote immune evasion. These results identify potential novel biomarkers of the tumor microenvironment as well as emphasize that targeting the UPR, and specifically the IRE1α axis, may serve an important target to bolster anti-tumor immunity