The tumor microenvironment is profoundly immunosuppressive. We show that multiple
tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the
PTEN (phosphatase and
tensin homolog)
lipid phosphatase. PTEN acted to stabilize Tregs in
tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN,
tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic
tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established
tumors, pharmacologic inhibition of PTEN after
chemotherapy or
immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and
tumors underwent rapid regression. Thus, the immunosuppressive milieu in
tumors must be actively maintained, and
tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.