AUTHOR=Flores-Santibañez Felipe , Rennen Sofie , Fernández Dominique , De Nolf Clint , Van De Velde Evelien , Gaete González Sandra , Fuentes Camila , Moreno Carolina , Figueroa Diego , Lladser Álvaro , Iwawaki Takao , Bono María Rosa , Janssens Sophie , Osorio Fabiola TITLE=Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1209588 DOI=10.3389/fimmu.2023.1209588 ISSN=1664-3224 ABSTRACT=

In cancer, activation of the IRE1/XBP1s axis of the unfolded protein response (UPR) promotes immunosuppression and tumor growth, by acting in cancer cells and tumor infiltrating immune cells. However, the role of IRE1/XBP1s in dendritic cells (DCs) in tumors, particularly in conventional type 1 DCs (cDC1s) which are cellular targets in immunotherapy, has not been fully elucidated. Here, we studied the role of IRE1/XBP1s in subcutaneous B16/B78 melanoma and MC38 tumors by generating loss-of-function models of IRE1 and/or XBP1s in DCs or in cDC1s. Data show that concomitant deletion of the RNase domain of IRE1 and XBP1s in DCs and cDC1s does not influence the kinetics of B16/B78 and MC38 tumor growth or the effector profile of tumor infiltrating T cells. A modest effect is observed in mice bearing single deletion of XBP1s in DCs, which showed slight acceleration of melanoma tumor growth and dysfunctional T cell responses, however, this effect was not recapitulated in animals lacking XBP1 only in cDC1s. Thus, evidence presented here argues against a general pro-tumorigenic role of the IRE1/XBP1s pathway in tumor associated DC subsets.