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

STAT3 signaling is fundamental to T cells, where it underlies basic cellular processes like metabolism and apoptosis, and specialized processes like 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 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, most notably 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.