Low-Dose Paclitaxel Prior to Intratumoral Dendritic Cell Vaccine Modulates Intratumoral Cytokine Network and Lung Cancer Growth

Abstract

Purpose-The main goal of this study was to provide the "proof-of-principle" that low-dose paclitaxel is able to change the tumor microenvironment and improve the outcome of intratumoral dendritic cell vaccine in a murine lung cancer model. Experimental Design-We evaluated the antitumor potential and changes in the intratumoral milieu of a combination of low-dose chemotherapy and dendritic cell vaccine in the Lewis lung carcinoma model in vivo.Results-The low-dose paclitaxel, which induced apoptosis in ~10% of tumor cells, was not toxic to bone marrow cells and dendritic cells and stimulated dendritic cell maturation and function in vitro. Although tumor cells inhibited dendritic cell differentiation in vitro, this immuno-suppressive effect was abrogated by the pretreatment of tumor cells with low-dose paclitaxel. Based on these data, we next tested whether pretreatment of tumor-bearing mice with low-dose paclitaxel in vivo would improve the antitumor potential of dendritic cell vaccine administered intratumorally. Significant inhibition of tumor growth in mice treated with low-dose paclitaxel plus intratumoral dendritic cell vaccine, associated with increased tumor infiltration by CD4 + and CD8 + T cells and elevated tumor-specific IFN-γ production by draining lymph node cells, was revealed. Using a novel intratumoral microdialysis technique and Luminex technology for collecting and characterizing soluble factors released within the tumor bed for several days in live freely moving animals, we showed that low-dose paclitaxel altered the cytokine network at the tumor site.Conclusions-Our data indicate that low-dose chemotherapy before intratumoral delivery of dendritic cells might be associated with beneficial alterations of the intratumoral microenvironment and thus support antitumor immunity.Lung cancer is the leading cause of cancer-related morbidity and mortality, resulting in more than 160,000 deaths per year in the United States and ~1.1 million worldwide. About 80% to 85% of lung cancer cases are non-small-cell lung cancer, and 65% of them have an Requests for reprints: Galina V. Shurin,

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…In this aspect, it was reported that PTX and other chemotherapeutic agents could up-regulate DC functions in vitro. 79 Studies from our group showed that low noncytotoxic concentrations of doxorubicin, methotrexate, mitomycin C and PTX directly up-regulate the ability of DCs to present antigens for Ag-specific T cells in vitro. These drugs significantly up-regulate the expression of CD80, CD86, CD40 and MHC class II molecules on DCs.…”

“…67 These observations supported the design of intratumoral administration of DCs after pretreatment of tumor-bearing mice with LDM PTX. 79 Such combination inhibits the s.c. development of murine lung cancer, increasing the infiltration of CD4þ and CD8þ cells. Increased survival was also correlated with release of IFN-c by draining lymph nodes lymphocytes and local production of MCP-1 and IP-10.…”

Radionuclide-embedded gold nanoparticles for enhanced dendritic cell-based cancer immunotherapy, sensitive and quantitative tracking of dendritic cells with PET and Cerenkov luminescence

“…[26][27][28] To create a DC-based cancer vaccine capable of generating LLC-associated antitumor immunity, the DCs were pulsed with whole lysates of LLC cells, as shown in Supplementary (Figures 3f-g). Antitumor effects were determined via caliper measurement and 18 Ffludeoxyglucose ( 18 F-FDG) PET/CT imaging.…”

In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway

“…For example, the antimicrotubule taxanes (paclitaxel and docetaxel) were found to trigger the production of cytokines by macrophages to activate other immune cells, such as DCs (15), NK cells (16), and CTLs, against tumors (16,17). Paclitaxel also reduced the number of regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and led to the augmentation of the functions of CD4 and CD8 T cells (16,17).…”

“…For example, the antimicrotubule taxanes (paclitaxel and docetaxel) were found to trigger the production of cytokines by macrophages to activate other immune cells, such as DCs (15), NK cells (16), and CTLs, against tumors (16,17). Paclitaxel also reduced the number of regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and led to the augmentation of the functions of CD4 and CD8 T cells (16,17). In other cases, DNA alkylating agents, such as cyclophosphamide and mafosfamide, in low doses selectively depleted Treg cells (18,19), caused an increase in effector T cells (Teff)/Treg cell ratios via up-regulation of the T helper (Th) 17 pathway (20), and improved the outcome of tumor vaccinations against cancer (21)(22)(23).…”