Tumor-infiltrating myeloid cells, such as dendritic cells (BMDC), are key regulators of tumor growth. However, the tumor-derived signals polarizing BMDC to a phenotype that subverts cell-mediated anti-tumor immunity have yet to be fully elucidated. Addressing this unresolved problem we show that the tumor unfolded protein response (UPR) can function in a cell-extrinsic manner via the transmission of ER stress (TERS) to BMDC. TERS-imprinted BMDC upregulate the production of pro-inflammatory, tumorigenic cytokines but also the immunosuppressive enzyme arginase. Importantly, they downregulate cross-presentation of high-affinity antigen and fail to effectively cross-prime CD8+ T cells, causing T cell activation without proliferation and similarly dominantly suppress cross-priming by bystander BMDC. Lastly, TERS-imprinted BMDC facilitate tumor growth in vivo with fewer tumor-infiltrating CD8+ T cells. In sum, we demonstrate that tumor-borne ER stress imprints ab initio BMDC to a phenotype that recapitulates several of the inflammatory/suppressive characteristics ascribed to tumor-infiltrating myeloid cells, highlighting the tumor UPR as a critical controller of anti-tumor immunity and a new target for immune modulation in cancer.
Evolutionarily conserved short (20-30 nucleotides) noncoding RNAs (microRNAs) are powerful regulators of gene expression in a variety of physiological and pathological processes. As such, means to efficiently modulate microRNA function constitute an important therapeutic opportunity. Here we demonstrate that primary B lymphocytes can be genetically programmed with nonviral plasmid DNA for the biogenesis and delivery of antisense sequences (anti-microRNA) against microRNA-150 (miR-150). Within 18 h of transfection with an anti-miR-150 construct, primary B lymphocytes secrete ∼3,000 copies of anti-miR-150 molecules per cell. Anti-miR-150 molecules released by B lymphocytes were internalized by CD8 T lymphocytes during cross-priming in vitro and in vivo, resulting in marked down-regulation of endogenous miR-150. However, such internalization was not observed in the absence of cross-priming. These results suggest that shuttling anti-miR-150 molecules from B lymphocytes to T cells requires the activation of receiver T cells via the antigen receptor. Finally, anti-miR-150 synthesized in B cells were secreted both as free and extracellular vesicleassociated fractions, but only extracellular vesicle-associated antimiR-150 were apparently taken up by CD8 T cells. Collectively, these data indicate that primary B lymphocytes represent an efficient platform for the synthesis and delivery of short, noncoding RNA, paving the way for an approach to immunogenomic therapies. microvesicles | immunotherapy
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