Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines

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 protu...

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Bibliographic Details
Published in:The Journal of experimental medicine 2018-03, Vol.215 (3), p.841-858
Main Authors: Miska, Jason, Lui, Jen Bon, Toomer, Kevin H, Devarajan, Priyadharshini, Cai, Xiaodong, Houghton, JeanMarie, Lopez, Diana M, Abreu, Maria T, Wang, Gaofeng, Chen, Zhibin
Format: Article
Language:English
Subjects:
Age
Anticancer properties
Autoimmune diseases
Autoimmunity
Cancer
CD4 antigen
CTLA-4 protein
Cytokines
Gastric cancer
Genetic transformation
Helper cells
Immune checkpoint
Immunity
Inflammation
Interleukin 13
Interleukin 4
Lymphocytes
Lymphocytes T
Malignancy
Microbiota
Mucosa
Stomach
Tumorigenesis
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Summary: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 1 or T 17 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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20171971