Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages.

摘要: We studied the effectiveness of monoclonal anti-CD40 + cytosine–phosphate–guanosine-containing oligodeoxynucleotide 1826 (CpG-ODN) immunotherapy (IT) in mice treated with multidrug chemotherapy (CT) consisting vincristine, cyclophosphamide and doxorubicin. Combining CT IT led to synergistic anti-tumour effects C57BL/6 established B16 melanoma or 9464D neuroblastoma. suppressed functions T cells natural killer (NK) cells, but primed naive peritoneal macrophages (Mφ) vitro stimulation lipopolysaccharide (LPS), resulting augmented nitric oxide (NO) production. IT, given after CT, did not restore responsiveness NK further activated Mφ secrete NO, interferon-γ (IFN-γ) interleukin (IL)-12p40 suppress proliferation tumour vitro. These functional changes were accompanied by immunophenotype alterations on Mφ, including up-regulation Gr-1. CD11b+F4/80+Mφ comprised major population tumour-infiltrating leucocytes. treatment up-regulated molecules associated M1 effector phenotype [CD40, CD80, CD86, histocompatibility complex (MHC) class II, IFN-γ, necrosis factor-α (TNF-α) IL-12] down-regulated M2 inhibitory (IL-4Rα, B7-H1, IL-4 IL-10) tumour-associated compared untreated controls. Together, results show that CpG-ODN synergize induction which are phenotypic repolarization Mφ.