Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, which is relatively resistant to anti-programmed cell death-1 (α-PD1) therapy, characterized as non-immunogenic, dense stroma and accumulation of M2 tumor-associated macrophages (TAMs). Despite progress in strategies to deplete extracellular matrix (ECM) and enhance tumor-cell immunogenicity, the combinatorial anti-cancer effects with α-PD1 need to be explored. Here, we applied doxorubicin hydrochloride liposome (Dox-L) as immunogenic cell death (ICD)-inducing nano-chemotherapy and used losartan as stroma-depleting agent to improve α-PD1 efficacy (Losartan + Dox-L + α-PD1). The results showed that losartan could cause ECM reduction, facilitating enhanced delivery of Dox-L and further dendritic cell (DC) maturation. Additionally, losartan could also alleviate hypoxia for TNBC, thus reprogramming pro-cancer M2 TAMs to anti-cancer M1 TAMs, successfully overcoming immune-suppressive microenvironment. These modifications led to a significant increase in T cells’ infiltration and augmented anti-tumor immunity as exemplified by the notable reduction in tumor size and lung metastases. In summary, our findings support that combined treatment of losartan with Dox-L normalizes immunological-cold microenvironment, improves immuno-stimulation and optimizes the efficacy of TNBC immunotherapy. A novel combinational strategy with FDA-approved compounds proposed by the study may potentially be useful in TNBC clinical treatment.

Co-delivery of gemcitabine and paclitaxel plus NanoCpG empowers chemoimmunotherapy of postoperative “cold” triple-negative breast cancer

“…5 f). In comparison, the chemo-immunotherapy of Dox-liposomes and αPD-1 did not prevent lung metastasis of 4T1 tumors, and only further combination with losartan as stroma-depleting agent could improve α-PD1 efficacy [ 49 ]. The MST of 4T1 tumor-bearing mice received chemo-immunotherapy of nanomedicines of PTX and STING agonists ADU-S100 was only 32 days with partially inhibited lung metastasis [ 37 ].…”

Engineering the glioblastoma microenvironment with bioactive nanoparticles for effective immunotherapy

“…180 Zhao et al combined losartan with anti-PD1 therapy to enhance the efficacy of chemo-immunotherapy for triple-negative breast cancer. 181 Using liposomes to encapsulate DOX, losartan, and α-PD1, the authors could normalize the TME, reducing stromal density, hypoxia, and immunosuppression. The components within the NP were able to reduce tumor size more than compared to only one or two drugs.…”

A landscape of recent advances in lipid nanoparticles and their translational potential for the treatment of solid tumors

“…189 A recent study found that the combination of liposomal doxorubicin, losartan, and anti-PD-1 therapy in 4T1 breast cancer mouse models showed improved immunogenicity and enhanced antitumor immune activity with overall reduced tumor volume. 151 In this case, doxorubicin causes immunogenic cell death, thereby facilitating further immune responses, while losartan reduces the density of the stroma, allowing the liposomal doxorubicin to better penetrate the tissue. Similarly, the combination of docetaxel and salvianolic acid B encapsulated in liposomal carriers improved the therapeutic outcomes in a mouse model of breast cancer.…”