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

ABSTRACT: 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 (ER?) 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 ER? activation in vivo. Collectively, our study proved combined treatment of ER? agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy.

SUBMITTER: Huang S 

PROVIDER: S-EPMC7476860 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature