Targeted therapies that inactivate MDSCs yet spare T-cell function enhance immune checkpoint blockade.

  • Major finding: Targeted therapies that inactivate MDSCs yet spare T-cell function enhance immune checkpoint blockade.

  • Mechanism: Blocking PI3K signaling disrupts cytokine cross-talk to promote MDSC depletion and inactivation.

  • Impact: Immune checkpoint blockade plus MDSC targeting may be beneficial in men with advanced prostate cancer.

Many patients with advanced prostate cancer treated with androgen deprivation therapy eventually succumb to metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint inhibitors including anti-CTLA4 and anti–PD-1/PD-L1 antibodies have proven successful in a variety of tumor types, but mCRPCs exhibit resistance, prompting Lu and colleagues to seek targeted therapies that might overcome this resistance. Targeted agents that had demonstrated activity in preclinical prostate cancer models or early clinical trials, or had immunomodulatory activity were screened in combination with immune checkpoint inhibitors (anti-CTLA4 plus anti–PD-1) in a mouse model of mCRPC to identify agents that might potentiate immune checkpoint blockade. All of the compounds had limited activity as single agents, but the tyrosine kinase inhibitor cabozantinib and the PI3K/mTOR inhibitor BEZ235 synergized with immune checkpoint blockade to slow the growth of primary and metastatic prostate tumors. Myeloid-derived suppressor cells (MDSC) are involved in tumor immune evasion, and granulocytic MDSCs (Gr-MDSC) have been shown to promote prostate cancer initiation and progression in mouse models. Accordingly, treatment with cabozantinib or BEZ235 reduced the number of MDSCs in the tumor microenvironment and attenuated their immunosuppressive activity, whereas immune checkpoint blockade increased the ratio of CD8+ T cells to immunosuppressive T regulatory cells, which was further enhanced by the addition of cabozantinib or BEZ235. Moreover, MDSC depletion sensitized mCRPCs to immune checkpoint blockade, indicating that checkpoint inhibitor resistance is mediated by MDSCs. Mechanistically, cabozantinib and BEZ235 suppressed PI3K signaling and reduced secretion of multiple MDSC-regulating cytokines to suppress Gr-MDSCS. In samples from patients with prostate cancer, Gr-MDSCs were negatively associated with CD8+ infiltrating T cells, further supporting a role for Gr-MDSCs in suppressing CD8+ T-cell activity. Altogether, these findings suggest that targeting MDSCs may improve the efficacy of immune checkpoint blockade, and combination immunotherapy warrants further investigation in patients with mCRPC.

Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 2017;543:728–32.