Antigen-derived peptides engage the ER stress sensor IRE1α to curb dendritic cell cross-presentation |
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| Authors: | Ofer Guttman Adrien Le Thomas Scot Marsters David A Lawrence Lauren Gutgesell Iratxe Zuazo-Gaztelu Jonathan M Harnoss Simone M Haag Aditya Murthy Geraldine Strasser Zora Modrusan Thomas Wu Ira Mellman Avi Ashkenazi |
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| Institution: | 1. Departments of Cancer Immunology, Genentech, South San Francisco, CA ; 2. Departments of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA ; 3. Departments of Oncology Bioinformatics, Genentech, South San Francisco, CA |
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| Abstract: | Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER), bind to major histocompatibility type I (MHC-I) protein complexes, and are transported to the cell surface for cross-presentation. DCs can exhibit activation of the ER stress sensor IRE1α without ER stress, but the underlying mechanism remains obscure. Here, we show that antigen-derived hydrophobic peptides can directly engage ER-resident IRE1α, masquerading as unfolded proteins. IRE1α activation depletes MHC-I heavy-chain mRNAs through regulated IRE1α-dependent decay (RIDD), curtailing antigen cross-presentation. In tumor-bearing mice, IRE1α disruption increased MHC-I expression on tumor-infiltrating DCs and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1α inhibition synergized with anti–PD-L1 antibody treatment to cause tumor regression. Our findings identify an unexpected cell-biological mechanism of antigen-driven IRE1α activation in DCs, revealing translational potential for cancer immunotherapy. |
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