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

Jason Miska, Jen Bon Lui, Kevin H. Toomer, Priyadharshini Devarajan, Xiaodong Cai, Jean Marie Houghton, Diana M Lopez, Maria T Abreu, Gaofeng Wang, Zhibin Chen

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 TH1 or TH17 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.

Original languageEnglish (US)
Pages (from-to)841-858
Number of pages18
JournalJournal of Experimental Medicine
Volume215
Issue number3
DOIs
StatePublished - Mar 1 2018

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Carcinogenesis
Cytokines
Inflammation
Stomach Neoplasms
Immunity
Stomach
Interleukin-4 Receptors
Interleukin-13
Microbiota
Autoimmunity
Epigenomics
Interleukin-4
Causality
T-Lymphocytes
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines. / Miska, Jason; Lui, Jen Bon; Toomer, Kevin H.; Devarajan, Priyadharshini; Cai, Xiaodong; Houghton, Jean Marie; Lopez, Diana M; Abreu, Maria T; Wang, Gaofeng; Chen, Zhibin.

In: Journal of Experimental Medicine, Vol. 215, No. 3, 01.03.2018, p. 841-858.

Research output: Contribution to journalArticle

Miska, Jason ; Lui, Jen Bon ; Toomer, Kevin H. ; Devarajan, Priyadharshini ; Cai, Xiaodong ; Houghton, Jean Marie ; Lopez, Diana M ; Abreu, Maria T ; Wang, Gaofeng ; Chen, Zhibin. / Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines. In: Journal of Experimental Medicine. 2018 ; Vol. 215, No. 3. pp. 841-858.
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