The mechanisms of immune-chemotherapy with nanocomplex codelivery of pTRP-2 and adjuvant of paclitaxel against melanoma

Abstract

Melanoma accounts for the highest proportion of all skin cancer deaths. Immune-chemotherapy has transformed anti-melanoma therapy and is a preferred first-line combination strategy for melanoma. We previously prepared dendritic cells (DCs) targeting the nanocomplex paclitaxel (PTX)-encapsulated sulfobutylether-β-cyclodextrin (SBE)/mannosylated N,N,N-trimethyl chitosan (mTMC)/DNA (PTX/SBE-DNA/Man-TMC) for the co-delivery of pTRP-2 DNA and adjuvant PTX. The nanocomplex PTX/SBE-DNA/Man-TMC promoted DC maturation and antigen presentation and spur potent anti-melanoma immunity. However, the mechanism by which PTX/SBE-DNA/Man-TMC regulates the biological functions of DCs and T lymphocytes is unknown. Therefore, we explored the underlying signaling pathways and mixed leukocyte reactions, resulting in enhanced T cell-mediated anti-tumor immunity. Interleukin-12 secretion from nanocomplex-pulsed mouse bone marrow-derived DCs was inhibited by treatment with Toll-like receptor 4 (TLR-4), nuclear factor kappa-B (NF-κB), and a specific blocker of p38 mitogen-activated protein kinase (MAPK). The results revealed that TLR-4, NF-κB, and MAPK signaling pathways were essential anti-tumor immune responses regulation factors. Furthermore, mixed leukocytes pulsed with PTX/SBE-DNA/Man-TMC induced tumor cell apoptosis and arrested the cell cycle in G0/G1, significantly promoting the synergy. Thus, we concluded that the mechanism driving the PTX/SBE-DNA/Man-TMC immune-chemotherapy synergistic effect was multifactorial.

Keywords:

• Mechanism
• melanoma
• MAPK
• NF-κB
• TLR-4
• apoptosis

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was financially supported by National Natural Science Foundation of China, Grant Numbers 81773673 and 81903555, Zhejiang Province Public Welfare Technology Application Research Project of China, Grant Numbers LGF19H300007 and LGF19H300006, Ningbo Welfare Technology Applied Research, Grant Numbers 202002N3158 and 2019C50036, and Key Laboratory of Ningbo, China, Grant Number 2016A22002.