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_H1 or T_H17 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.

遗传易感性人类CTLA4功能不全与胃癌的发展有关，这与CTLA4在抑制抗肿瘤免疫力方面的原型作用矛盾。CTLA4是针对自身免疫性疾病的关键免疫检查点。自身免疫与肿瘤或抗肿瘤活性有关。在这里，我们显示CTLA4功能不全通过宿主内源性免疫失调而不是微生物群引发的炎症在小鼠胃中引发从头肿瘤发生，与年龄相关的进展为恶性肿瘤并伴随表观遗传失调。炎性肿瘤发生需要CD4 T细胞，但不需要T _H 1或T _H17个子集。IL-4和IL-13或IL-4受体α的缺乏打破了炎症与肿瘤发生开始之间的联系。这项研究建立了CTLA4功能不全在胃癌中的因果关系，并揭示了2型炎症在启动胃上皮转化中的作用。这些发现表明，通过阻断致癌的2型炎症，同时保留1型抗肿瘤免疫力，可能会改善免疫疗法。