Depletion of tumor-associated macrophages by melittin-dKLA enhances anti PD-L1 mediated anti-tumor effects in breast cancer models

Abstract

Abstract Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment and known to have an M2-like pro-metastatic phenotype. M2-like TAMs directly support migration, adhesion and invasion of tumor cells. Therefore, M2-like TAMs are promising targets for inhibiting cancer. Anti-PD-1/PD-L1 immunotherapies have been used for an inhibition of PD-1/PD-L1 mediated T cell exhaustion in various cancers such as lymphoma, melanoma, and renal cancer with remarkable clinical success, however, most breast cancer patients have been reported to show resistances or short response durations. A lot of researches have been reported that targeting TAMs from tumor microenvironment synergized the effect of PD-1/PD-L1 therapies, suggesting that TAMs are major causes of PD-1/PD-L1 resistance. Previously, I have developed MEL-dKLA, a hybrid peptide that was conjugated with melittin (MEL) and pro-apoptotic peptide dKLA to eliminate M2 like TAM. In this study, I investigated whether removal of M2-like TAMs by MEL-dKLA enhanced the anti-cancer effect of PD-L1 antibodies in 4T1 breast cancer. Combination therapy with MEL-dKLA and anti PD-L1 delays tumor growth and increases survival. It inhibits the exhausted CD8+ T cell population in tumors, enabling them to perform cytotoxic functions. Simultaneous treatment with MEL-dKLA and anti PD-L1 reduced the contact area between TAM and CD8+ T cells in the tumor microenvironment. Therefore, these results suggested that MEL-dKLA and anti PD-L1 combination therapy will be promising for breast cancer treatments.