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

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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 Stk11 (which encodes LKB1) display signatures of pathogenic IL-17–producing CD4 + T helper 17 (T H 17) cells. LKB1 constrains T cell inflammatory potential, as Stk11 /LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17–producing T cell lineages (CD4 + T H 17 and CD8 + T c 17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)–dependent signaling drives pathogenic T H 17 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.