Nanoassemblies loaded with low-dose paclitaxel can enhance the response of lung cancer immunotherapy by activating dendritic cells.

Background: The immune tolerance of the tumor immune microenvironment (TIME) restricts the response to immune checkpoint inhibitors (ICIs). Targeted activation of dendritic cells (DCs) in the TIME seems to be a scheme for improving the therapeutic effect of ICIs treatment. The purpose of this study was to utilize nanotechnology to reprogram the immunosuppressive tumor immune microenvironment , improving the response of ICIs to lung cancer.

Methods: In this study, a folic acid (FA)-modified nanoassembly (NA) loaded with low-dose paclitaxel (PTX) (FA-PTX NA), self-assembled by distearoylphosphatidylethanolamine-methoxy polyethylene glycol 2000-folic acid (DSPE-mPEG2000-FA) and PTX, was designed to reprogram the DC function of the TIME to sensitize cells to cancer immunotherapy. The characteristics of FA-PTX NAs were studied, and the cytotoxicity, cellular uptake, and DC stimulation of FA-PTX NAs were evaluated using a Lewis lung carcinoma (LLC) cell line and bone marrow-derived cells (BMDCs). Following this, the effect of the reprogrammed TIME and on the sensitization to immunotherapy were examined in a C57BL/6 mouse LLC subcutaneous xenograft model.

Results: The prepared FA-PTX NAs exhibited a slightly negative surface charge, appropriate size and shape, good drug release profiles, and high drug encapsulation efficiency and blood compatibility. The FA-PTX NAs were effectively uptaken by bone BMDCs, increasing the activation and expression of the costimulatory factor of BMDCs . In the LLC xenograft model treated with intravenous injection of FA-PTX NAs, the numbers of CD4 and CD8 T cells in the TIME increased significantly, the killing activity of tumor-specific cytotoxic T lymphocytes (CTLs) was significantly enhanced, and at the same time, the concentration of transforming growth factor β (TGF-β) decreased significantly. Furthermore, the infiltrated CD8 T cells in TIME were mainly distributed in the tumor parenchyma. The combination of FA-PTX NAs and ICIs effectively inhibited the growth of LLC xenograft tumor, demonstrating a greater effect than that of ICIs alone. Moreover, it was found that apoptosis induction, increase in CD4 and CD8 T-cell infiltration, and improvement in the distribution of CD8 T cells were involved in the anticancer mechanism of this combination treatment.

Conclusions: The NA loaded with low-dose PTX can reprogram the DC function in the TIME and exert a synergistic anticancer effect with ICIs in lung cancer treatment. Increased sensitization to ICI therapy as stimulated by PTX-enhanced NAs has potential applications in lung cancer immunotherapy.