Novel cancer immunotherapy using rational combinations of B7-H1 blockade, Treg depletion and estrogen receptor beta signaling (165.17)

Abstract

Abstract We recently showed that B7-H1 blockade in mouse models for B16 melanoma and ID8 ovarian carcinoma worked better in females versus males through reduced regulatory T cell (Treg) function. We now show that B7-H1 blunts estrogen-mediated mTOR activation in differentiating Tregs as the mechanism. When we differentiated naïve CD4+ T cells into Tregs in vitro, estrogen reduced Treg numbers and function only if B7-H1 was blocked. The effect was equivalent in males and females. Treg depletion for cancer immunotherapy is promising but hampered by rapid Treg regeneration. Because estrogen signals reduced Treg generation when B7-H1 was blocked, we hypothesized that B7-H1 block during therapeutic Treg depletion would improve clinical efficacy of either individual approach, and that estrogen signals would further boost combination effects. We then showed that estrogen effects were through estrogen receptor beta, suggesting that estrogen receptor beta agonists (in human clinical trials with promising results) could boost Treg depletion with B7-H1 blockade as cancer immunotherapy. In a proof-of-concept experiment, in B16 melanoma challenge, estrogen improved tumor resistance in B7-H1 KO males but not WT males through reduced Treg function. B7-H1 blockade plus estrogen also improved anti-CTLA-4 effects, suggesting rational combinations of immune blockade, Treg depletion and estrogen signals as novel cancer immunotherapies.