TY - JOUR
T1 - Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines
AU - Miska, Jason
AU - Lui, Jen Bon
AU - Toomer, Kevin H.
AU - Devarajan, Priyadharshini
AU - Cai, Xiaodong
AU - Houghton, Jean Marie
AU - Lopez, Diana M.
AU - Abreu, Maria T.
AU - Wang, Gaofeng
AU - Chen, Zhibin
N1 - Publisher Copyright:
© 2018 Miska et al.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=85042864225&partnerID=8YFLogxK
U2 - 10.1084/jem.20171971
DO - 10.1084/jem.20171971
M3 - Article
C2 - 29374027
AN - SCOPUS:85042864225
SN - 0022-1007
VL - 215
SP - 841
EP - 858
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -