The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression

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SUMMARYTen-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found thatTet2expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients and that this increased expression is dependent on an IL-1R-MyD88 pathway. Ablation ofTet2in myeloid cells suppressed melanoma growthin vivoand shifted the immunosuppressive gene expression program in tumor-associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function. This resulted in increased numbers of effector T cells in the tumor, and T cell depletion abolished the reduced tumor growth observed upon myeloid-specific deletion ofTet2. Our findings reveal a non-cell-intrinsic, tumor-promoting function for Tet2 and suggest that Tet2 may present a therapeutic target for the treatment of non-hematologic malignancies.Graphical AbstractHighlightsDeletion of Tet2 in myeloid cells reduces melanoma tumor burdenTet2 expression is induced via the IL-1R-MyD88 axis in tumor-associated macrophagesTet2 maintains myeloid immunosuppressive function and the associated genetic programMyeloid-specific Tet2 deletion results in higher numbers of tumor-infiltrating T cellsThe DNA methylcytosine dioxygenase Tet2 functions as a tumor suppressor in multiple contexts, including hematopoietic malignancies. Pan et al. now reveal a tumor-promoting role for Tet2, whereby Tet2 functions to sustain an immunosuppressive program in myeloid cells that in turn dampens the anti-tumor T cell response.

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