Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 215, Issue 3, Pages 841-858Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171971
Keywords
-
Categories
Funding
- National Institutes of Health National Cancer Institute [1R21CA178675-01]
- American Gastroenterological Association-R. Robert & Sally D. Funderburg Research Award in Gastric Cancer
Ask authors/readers for more resources
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 T(H)1 or T(H)17 subsets. Deficiencies in IL-4 and IL-13 or IL-4 receptor alpha 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available