Pharmacological Activation of Estrogen Receptor Beta Overcomes Tumor Resistance to Immune Checkpoint Blockade Therapy

The emerging immune checkpoint blockade (ICB) therapy has ushered the cancer therapeutics field into an era of immunotherapy. Although ICB treatment provides remarkable clinical responses in a subset of patients with cancer, this regimen fails to extend survival in a large proportion of patients. Here, we found that a combined treatment of estrogen receptor beta (ERβ) agonist and PD-1 antibody treatment improved therapeutic efficacy in mouse tumor models, compared with monotherapies, by reducing infiltration of myeloid-derived suppressor cells (MDSCs) and increasing CD8⁺ T cells in tumors. Mechanistically, LY500307 treatment reduced tumor-derived CSF1 and decreased infiltration of CSF1R⁺ MDSCs in the tumor bed. CSF1 released by tumor cells induced CSF1R⁺ MDSC chemotaxis in vitro and blockade of CSF1R demonstrated similar therapeutic effects as ERβ activation in vivo. Collectively, our study proved combined treatment of ERβ agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy.