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Cell-extrinsic effects of tumor endoplasmic reticulum stress on myeloid cells


The unfolded protein response (UPR) is an evolutionarily- conserved group of signaling pathways that eukaryotic cells use to adapt to periods of perturbed endoplasmic reticulum (ER) function caused by the accumulation of un/ misfolded proteins the ER lumen. Tumor cells undergo a constitutive UPR to survive the ER stress-inducing noxae within their microenvironment, such as hypoxia and nutrient deprivation. Elements of the tumor UPR have been shown to be key cell-intrinsic mechanisms of tumor survival but only few reports have considered the cell- extrinsic influence of the tumor UPR. Tumor-infiltrating myeloid cells, such as macrophages and dendritic cells, are key players in the cell-extrinsic regulation of tumor growth. Upon entering the tumor microenvironment, however, these cells are polarized to an inflammatory/suppressive phenotype that exacerbate the pro-inflammatory nature of the tumor microenvironment while concomitantly suppressing cell-mediated anti-tumor immune responses. However, the tumor-derived signals driving this mixed inflammatory/ suppressive phenotype have yet to be elucidated. Herein, we show that the tumor cell UPR can function in a cell- extrinsic manner by transmitting ER stress to myeloid cells that infiltrate the tumor microenvironment, a phenomenon we have termed TERS (transmissible ER stress). TERS-imprinted myeloid cells upregulate production of tumorigenic, inflammatory cytokines but also upregulate immunosuppressive markers, culminating in a pro- inflammatory/suppressive phenotype. In macrophages, TERS is sensed, in part, by TLR4. Furthermore, TERS-imprinted myeloid cells display a unique functional phenotype, upregulating costimulatory molecule expression, antigen- presentation machinery, while downregulating effective high-affinity antigen cross-presentation. We demonstrate that TERS-imprinted BMDC do not effectively prime CD8⁺ T cells, causing activation without proliferation, in part due to increased arginase activity. CD8⁺ T cells cross- primed by TERS-imprinted BMDC display a regulatory phenotype and abnormally highly splicing of Xbp-1. We also show that TERS-imprinted BMDC can also dominantly suppress the proper cross-priming function of normal bystander BMDC. Lastly, TERS-imprinted BMDC facilitate tumor growth in vivo, even promoting the transient escape of highly immunogenic tumor cells. Taken together, we demonstrate the ab initio generation of tumor-imprinted myeloid cells that have many of the inflammatory/suppressive characteristics of previously-described tumor-infiltrating myeloid cells and bring to the forefront the tumor UPR as a fundamental driver of myeloid cell polarization

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