Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases

• DOI: 10.1126/science.aao4908
• Publication Date: 2018-05-17T18:00:17Z
• Authors: Arnaud Pommier; Naishitha Anaparthy; Nicoletta Memos; Z. Larkin Kelley; Alizée Gouronnec; Ran Yan; Cédric Auffray; Jean Albrengues; Mikala Egeblad; Christine A. Iaco...; Scott K. Lyons; Douglas T. Fearon
• Keywords: XBP1

The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection their primary tumor. We found that livers from and mice PDA harbor single disseminated cancer cells (DCCs) lacking expression cytokeratin 19 (CK19) major histocompatibility complex class I (MHCI). created a mouse model to determine how these DCCs develop. Intraportal injection immunogenic into preimmunized seeded only single, nonreplicating were CK19- MHCI- exhibited an endoplasmic reticulum (ER) stress response but paradoxically lacked both inositol-requiring enzyme 1α activation the spliced form transcription factor XBP1 (XBP1s). Inducible XBP1s in DCCs, combination T cell depletion, stimulated outgrowth macrometastatic lesions expressed CK19 MHCI. Thus, unresolved ER enables escape immunity establish latent metastases.