Abstract
The IRE1α/XBP1s signaling pathway is an arm of the unfolded protein response (UPR) that safe guards the fidelity of the cellular proteome during endoplasmic reticulum (ER) stress. IRE1α has also emerged as a key regulator of dendritic cell (DC) homeostasis where it controls key features including the cross-presentation of dead cell-associated antigens. This aspect is highly applicable to the field of antitumor immunity, as representative tumor antigens are likely to be contained within dying cancer cells. Thus, the aim of this work is to elucidate the role of IRE1α signaling in innate recognition and antigen-presentation of melanoma-associated antigens to CD8+ T cells. We found that melanoma cell lysates (MEL) were potent activators of the IRE1α/ XBP1s pathway and additional members of the UPR including CHOP and BiP, in various cultures of bone marrow derived DCs (BMDCs). To assess the role of IRE1α in the recognition of MEL by BMDCs we used the aldehydes 4µ8C and STF-083010, two pharmacological inhibitors of the IRE1α RNAse domain. BMDCs stimulated with MEL in presence of 4µ8C produced lower levels of pro-inflammatory cytokines and showed curtailed abilities to cross-present MEL-associated antigens to CD8+ T cells. Remarkably, IRE1α blockade specifically decreased cross-presentation of MEL-associated antigens without interfering with the phagocytic capacity of DCs, endogenous MHC-I antigen presentation or presentation of tumor antigens via MHC-II. Furthermore, BMDCs expressing a mutant isoform IRE1α that lacks the RNase domain were less efficient at inducing CD8+ T cell proliferation to a melanoma-as-sociated antigen in vivo. Our data indicates that activation of the IRE1α/XBP1s axis in BMDCs promotes CD8+ T cell priming to melanoma antigens. Knowledge derived from this study may be considered in the design of DC-based vaccines for cancer immunotherapy.
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call