IL-17 links the tumor suppressor LKB1 to gastrointestinal inflammation and polyposis.

Abstract

Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp growth. GI tumors from mice bearing heterozygous mutations in <i>Stk11</i> (which encodes LKB1) display signatures of pathogenic IL-17-producing CD4⁺ T helper 17 (T_H17) cells. LKB1 constrains T cell inflammatory potential, as <i>Stk11</i>/LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17-producing T cell lineages (CD4⁺ T_H17 and CD8⁺ T_c17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)-dependent signaling drives pathogenic T_H17 cell programs downstream of LKB1 haploinsufficiency. Targeting this circuit via CRTC2 deletion or IL-17 blockade antagonizes GI polyp growth in mouse models of Peutz-Jeghers syndrome. These findings establish LKB1 as a gatekeeper of inflammatory type 3 (IL-17-dependent) T cell responses and identify a CRTC2-IL-17 signaling axis that can be targeted therapeutically to block the growth of LKB1 mutant GI tumors.