Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity

• Published in: Frontiers in immunology Vol. 14; p. 1209588
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 06.06.2023
• Subjects: Adaptive Immunity; Animals; Dendritic Cells; Endoribonucleases - genetics; Endoribonucleases - metabolism; immunity; Immunology; IRE1; melanoma; Melanoma, Experimental - metabolism; Mice; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Ribonuclease, Pancreatic - metabolism; Ribonucleases - metabolism; unfolded protein response; XBP1; antitumor immune response; cDC1; unfolded protein response; XBP1; dendritic cells; IRE1; melanoma; immunity
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1209588

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.