UC San Diego

Transmissible endoplasmic reticulum (ER) stress is emerging as a cell non-autonomous mechanism that drives the failure of immune competency within the tumor microenvironment (TME). Reprogramming of myeloid cell infiltrate within the TME to a mixed pro-inflammatory/immune suppressive phenotype is at the root of this immune dysregulation, and we show here that the unfolded protein response (UPR) is a possible origin of these events. The inositol-requiring enzyme 1 (IRE1a) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the upregulation of IL-6, IL-23, Arginase1, as well as surface expression of CD86 and PD-L1. Macrophages in which the IRE1a-Xbp1 axis is blocked pharmacologically or deleted genetically have significantly reduced polarization, CD86 and PD-L1 expression. Mice with IRE1a- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. RNASeq analysis showed that bone marrow derived macrophages with IRE1a deletion lose the integrity of the gene connectivity characteristic of regulated IRE1a-dependent decay (RIDD) and fail to activate PD-L1 gene expression. Thus, the IRE1a-Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immunosurveillance.