T-cell lymphoma-associated STAT3 variants impose a type 1 regulatory-like phenotype

STAT3 signaling is fundamental to T cells, where it underlies basic cellular processes like metabolism and apoptosis, as well as specialized processes like effector differentiation and cytokine production. However, mutations of STAT3 are strikingly prevalent in T-cell cancers, and aberrant or excessive STAT3 signaling is thought to mobilize cellular pathways that encourage malignancy. To better understand how STAT3 mutations drive T-cell cancers, we compared two frequent cancer-associated variants, Y640F and N647I, at the cellular and molecular levels. Using a retrogenic system, we demonstrate that they are qualitatively similar yet quantitatively distinct; each bears a gain-of-function phenotype, but Y640F has greater transcriptome-wide effects. We also discovered that these and other common STAT3 mutants invoke a T regulatory 1 (Tr1) gene program characterized by expression of IL-10 and other factors that dampen T-cell responses, including LAG3 and CD39. Importantly, “Tr1 skewing” is evident in both mouse T cells expressing cancer-associated STAT3 variants and humans afflicted with T-cell malignancies. These studies advance current understanding of how cancer-associated mutations impact STAT3 function and reveal anti-inflammatory properties that may help transformed T cells persist, expand, and/or avoid eradication.