Albumin nanoparticle containing a PI3Kγ inhibitor and paclitaxel in combination with α-PD1 induces tumor remission of breast cancer in mice

Abstract

Immunomodulators that remodel the tumor immunosuppressive microenvironment have been combined with anti–programmed death 1 (α-PD1) or anti–programmed death ligand 1 (α-PDL1) immunotherapy but have shown limited success in clinical trials. However, therapeutic strategies to modulate the immunosuppressive microenvironment of lymph nodes have been largely overlooked. Here, we designed an albumin nanoparticle, Nano-PI, containing the immunomodulators PI3Kγ inhibitor (IPI-549) and paclitaxel (PTX). We treated two breast cancer mouse models with Nano-PI in combination with α-PD1, which remodeled the tumor microenvironment in both lymph nodes and tumors. This combination achieved long-term tumor remission in mouse models and eliminated lung metastases. PTX combined with IPI-549 enabled the formation of a stable nanoparticle and enhanced the repolarization of M2 to M1 macrophages. Nano-PI not only enhanced the delivery of both immunomodulators to lymph nodes and tumors but also improved the drug accumulation in the macrophages of these two tissues. Immune cell profiling revealed that the combination of Nano-PI with α-PD1 remodeled the immune microenvironment by polarizing M2 to M1 macrophages, increasing CD4 ⁺ and CD8 ⁺ T cells, B cells, and dendritic cells, decreasing regulatory T cells, and preventing T cell exhaustion. Our data suggest that Nano-PI in combination with α-PD1 modulates the immune microenvironment in both lymph nodes and tumors to achieve long-term remission in mice with metastatic breast cancer, and represents a promising candidate for future clinical trials.

Abstract

Nanomedicine remodels immunosuppressive microenvironment in both lymph nodes and tumors to achieve long-term tumor remission in breast cancer models.

Honey I shrunk the immunotherapy

Triple-negative breast cancer is known to have an immunosuppressive tumor microenvironment, which results in poor response to combined immunotherapy and chemotherapy. To overcome this, Song et al. focused on improving drug delivery using albumin-encapsulated nanoparticles containing a PI3Kγ inhibitor and paclitaxel, called Nano-PI, targeting tumors and adjacent lymph nodes. They combined Nano-PI with anti–programmed death 1 (α-PD1) to treat mouse models of breast cancer and induced long-term tumor remission. Their combination treatment remodeled the tumor microenvironment by repolarizing immunosuppressive M2 macrophages to immune-promoting M1 macrophages. This study represents a promising step forward in immunotherapy treatment for breast cancer and warrants further clinical investigation.