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

Abstract

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

The impact of hypoxia on tumor-associated macrophages

“…There are several other examples of successful combinations of well-established treatment regimens with immunotherapy. In B16 melanoma and 9464D neuroblastoma, multidrug chemotherapy (vincristine, cyclophosphamide, and doxorubicin) combined with immunotherapy (anti-CD40 and cytosine-phosphateguanosine-containing oligodeoxynucleotide 1826 [CpG-ODN]) enhanced NO, IFN-γ, and IL-12p40 secretion by macrophages, leading to a strong antitumor response (104).…”

The Impact of Chemotherapy and Radiation Therapy on the Remodeling of Acellular Dermal Matrices in Staged, Prosthetic Breast Reconstruction

“…Fibrous encapsulation is mediated in part by an increase in the proportion of M1 macrophages that promote scar formation, versus M2 macrophages that facilitate ADM remodeling 51, 52, 67 but also suppress natural killer and T-cells 68–72 . In fact, several chemotherapeutic regimens used in breast cancer therapy including cyclophosphamide 73 , doxorubicin 74 , and paclitaxel disrupt the pro-tumor properties of M2 macrophages 75 . By contrast, an increased concentration of M2 macrophages hinders the chemotherapeutic response in both a murine breast cancer model 76 , and clinically 77 .…”

Nanoparticulate immunotherapy for cancer

“…Additionally, polarizing M2 phenotype into M1 phenotype via TLR agonist is another strategy to improve efficacy in anti-tumor immunotherapy. For example, utilizing the CpG (TLR-9 agonist) in conjunction with anti-CD40 Abs has been shown to rapidly induce production of pro-inflammatory cytokines leading to polarization of M2 to M1 macrophages and subsequently, accelerated suppression of tumor growth [91].…”