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

被引：228

作者：

Pommier, Arnaud ^{[1
]}

Anaparthy, Naishitha ^{[1
,2
]}

Memos, Nicoletta ^{[1
]}

Kelley, Z. Larkin ^{[3
]}

Gouronnec, Alizee ^{[1
]}

Yan, Ran ^{[1
]}

Auffray, Cedric ^{[4
]}

Albrengues, Jean ^{[1
]}

Egeblad, Mikala ^{[1
]}

Iacobuzio-Donahue, Christine A. ^{[5
]}

Lyons, Scott K. ^{[1
]}

Fearon, Douglas T. ^{[1
,3
,6
]}

机构：

[1] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[2] SUNY Stony Brook, Dept Mol & Cellular Biol, Stony Brook, NY 11794 USA

[3] Weill Cornell Med, New York, NY 10065 USA

[4] Paris Descartes Univ, CNRS, Inst Cochin, INSERM,UMR8104,U1016, F-75014 Paris, France

[5] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA

[6] Univ Cambridge, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England

来源：

SCIENCE | 2018年 / 360卷 / 6394期

关键词：

UNFOLDED PROTEIN RESPONSE; MHC CLASS-I; TUMOR DORMANCY; CELL DORMANCY; INHIBITION; EXPRESSION; ADENOCARCINOMA; IMMUNOTHERAPY; PROGRESSION; MODELS;

D O I：

10.1126/science.aao4908

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 1a 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.

引用

页码：1202 / +

页数：10

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