Journal Article

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

Yan, Ran, Anaparthy, Naishitha, Fearon, Douglas T., Pommier, Arnaud, Memos, Nicoletta, Iacobuzio-Donahue, Christine A., Albrengues, Jean, Kelley, Z. Larkin, Egeblad, Mikala, Auffray, Cédric, Lyons, Scott K., Gouronnec, Alizée

2018

Overview

Most patients with pancreatic ductal adenocarcinoma (PDA) develop liver metastases after surgical removal of their primary tumor. These metastases are thought to potentially arise from quiescent disseminated cancer cells, likely present at the time of surgery, which evade elimination by the immune system. Pommier et al. explored how these quiescent cells survive by analyzing mouse models and tissue samples from patients with PDA. They found that disseminated cancer cells do not express a cell surface molecule that triggers killing by T cells. This phenotypic feature is linked to their inability to resolve endoplasmic reticulum stress. When this stress is resolved, the disseminated cells begin proliferating and form metastases. Science , this issue p. eaao4908 Chronic endoplasmic reticulum stress allows disseminated cancer cells that form metastases to evade immune control. The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single disseminated cancer cells (DCCs) lacking expression of cytokeratin 19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intraportal injection of immunogenic PDA cells into preimmunized mice seeded livers only with single, nonreplicating DCCs that were CK19 – and MHCI – . The DCCs exhibited an endoplasmic reticulum (ER) stress response but paradoxically lacked both inositol-requiring enzyme 1α activation and expression of the spliced form of transcription factor XBP1 (XBP1s). Inducible expression of XBP1s in DCCs, in combination with T cell depletion, stimulated the outgrowth of macrometastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent metastases.

• Publisher: The American Association for the Advancement of Science,American Association for the Advancement of Science (AAAS)
• Subject: Activation / Adaptive immunity / Adenocarcinoma / Allografts / Animal models / Animals / Cancer / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - secondary / CD8 antigen / Cell death / Cell proliferation / Cell surface / Cellular stress response / Cytokeratin / Death / Depletion / Endoplasmic reticulum / Endoplasmic Reticulum Stress - immunology / Endoribonucleases - genetics / Endoribonucleases - metabolism / Enzymes / Gene sequencing / Genes, MHC Class I / Genetic Engineering / Genotype & phenotype / Humans / Immune response / Immune system / Immunity / Immunogenicity / Immunology / Injection / Inositol / Keratin-19 - metabolism / Kinases / Latency / Lesions / Life Sciences / Liver / Liver Neoplasms - immunology / Liver Neoplasms - secondary / Lymphocyte Depletion / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Metastases / Metastasis / Mice / Mice, Inbred C57BL / Molecular chains / Neoplasms, Experimental - genetics / Neoplasms, Experimental - immunology / Neoplasms, Experimental - secondary / Organic chemistry / Pancreatic cancer / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - pathology / Patients / Pharmacology / Phenotypes / Protein folding / Protein kinase / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Proteins / Ribonucleic acid / RNA / Stress response / Stresses / Surgery / Survival / T-Lymphocytes - immunology / Tumor Escape / Tumors / X-Box Binding Protein 1 - genetics / X-Box Binding Protein 1 - metabolism