Cancer creates a peculiar inflammatory environment enriched for transcription factors with a negative influence on adaptive immunity. In this issue of the JCI, Watkins and colleagues identify Foxo3 as a master regulator of the tolerogenic program in tumor-associated, plasmacytoid DCs (pDCs). Foxo3 enables pDCs to induce tolerance in tumor antigen-specific CD8+ T cells, turning them into regulatory lymphocytes capable of inhibiting nearby CD8+ T lymphocytes. Provision of tumor-specific CD4+ T helper cells interrupts this circuit by inhibiting Foxo3 expression and fully licensing the antigen-presenting ability of pDCs. These data identify a new target for therapeutic intervention and provide insight into the transcription factor interplay in myeloid cells recruited to the cancer microenvironment.
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