Initiation of Inflammatory Tumorigenesis by CTLA4 Insufficiency Due to Type 2 Cytokines

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2018 Jan 28

PMID 29374027

Citations 13

Authors

Jason Miska

Jen Bon Lui

Kevin H Toomer

Priyadharshini Devarajan

Xiaodong Cai

JeanMarie Houghton

Diana M Lopez

Maria T Abreu

Gaofeng Wang

Zhibin Chen

Affiliations

Soon will be listed here.

Abstract

Genetically predisposed CTLA4 insufficiency in humans is associated with gastric cancer development, which is paradoxical to the prototypical role of CTLA4 in suppressing antitumor immunity. CTLA4 is a critical immune checkpoint against autoimmune disorders. Autoimmunity has been implicated in protumor or antitumor activities. Here, we show that CTLA4 insufficiency initiates de novo tumorigenesis in the mouse stomach through inflammation triggered by host-intrinsic immune dysregulation rather than microbiota, with age-associated progression to malignancy accompanied by epigenetic dysregulation. The inflammatory tumorigenesis required CD4 T cells, but not the T1 or T17 subsets. Deficiencies in IL-4 and IL-13 or IL-4 receptor α broke the link between inflammation and initiation of tumorigenesis. This study establishes the causality of CTLA4 insufficiency in gastric cancer and uncovers a role of type 2 inflammation in initiating gastric epithelial transformation. These findings suggest possible improvement of immune therapies by blocking tumorigenic type 2 inflammation while preserving antitumor type 1 immunity.

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