Triple negative breast cancer (TNBC) does not respond to checkpoint blockade immunotherapy as a result of immunosuppressive tumor microenvironment. To remodel the tumor microenvironment, we developed a liposome formulation to deliver a potential immunogenic cell death (ICD) inducing agent, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG, or tanespimycin), in a tumor targeted manner to reverse the immunosuppressive microenvironment and facilitate the checkpoint blockade immunotherapy. The 17-AAG liposomes was prepared by thin film dispersion methods. The orthotopic 4T1 murine triple negative breast cancer model was studied. 17-AAG delivered by liposome remodeled the immunosuppressive microenvironment, significantly increased tumor infiltrating T cells, lowered the hypoxia level, decreased the suppressive lymphocytes such as tumor associated macrophages and myeloid derived suppressor cells in the tumor microenvironment. In addition, real-time PCR analysis revealed that chemokines and cytokines with immunosuppressive properties were notably reduced, which further facilitated the T cell mediated immunotherapy. Despite the fact that low dose 17-AAG liposomes demonstrated a limited therapeutic effect alone on 4T1 tumor, promising efficacy was observed when 17-AAG liposomes combined with checkpoint blockade immunotherapy. Taken together, 17-AAG liposomes could remodel the immunosuppressive microenvironment of triple negative breast cancer and facilitate the checkpoint blockade immunotherapy.
Keywords: 17-AAG; Checkpoint blockade immunotherapy; Hsp90 inhibitor; Immunogenic cell death; Triple negative breast cancer; Tumor microenvironment.
Published by Elsevier B.V.