Adjuvant-mediated tumor regression and tumor-specific cytotoxic response are impaired in MyD88-deficient mice.

Abstract

The Mycobacterium bovis bacillus Calmette-Guérin cell-wall skeleton (BCG-CWS) activates Toll-like receptor (TLR) 2 and TLR4, but unlike the typical TLR4 agonist bacterial lipopolysaccharide barely induces type 1 IFN. BCG-CWS has been used for adjuvant immunotherapy for patients with cancer. We investigated the adjuvant potential of BCG-CWS for induction of CTLs subsequent to TLR-mediated dendritic cell (DC) maturation, using a syngeneic mouse tumor model (B16 melanoma in C57BL/6). We evaluated the retardation of tumor growth and cytotoxic response in wild-type and MyD88-/- mice immunized with tumor debris and/or BCG-CWS. Delays in tumor growth and cytotoxic response were induced by immunization with a mixture of BCG-CWS emulsion and the tumor. BCG-CWS was capable of activating DCs ex vivo by the criteria of CD80/CD86 up-regulation and cytokine (interleukin-12, tumor necrosis factor-alpha) induction. Efficient tumor suppression and ex vivo cytokine induction did not occur in MyD88-deficient mice and cells, suggesting that the MyD88 adapter is crucial for induction of tumor cytotoxicity. Because TLR4 is involved in both MyD88-dependent and -independent pathways and the latter affects DC maturation, our findings indicate that both pathways cooperate to induce CTL-based tumor immunity.

• Authors: Takashi Akazawa, Hisayo Masuda, Yoshiko Saeki, Misako Matsumoto, Kiyoshi Takeda, Kunio Tsujimura, Kiyotaka Kuzushima, Toshitada Takahashi, Ichiro Azuma, Shizuo Akira, Kumao Toyoshima, Tsukasa Seya
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 2 Pg. 757-64 (Jan 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 14744795 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antigens, Differentiation
• Antigens, Surface
• BCG Vaccine
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Receptors, Immunologic

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Antigens, Differentiation (genetics, physiology)
• Antigens, Surface (analysis)
• BCG Vaccine
• Combined Modality Therapy
• Female
• Flow Cytometry
• Immunotherapy
• Male
• Melanoma, Experimental (immunology, therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88
• Receptors, Immunologic (deficiency, genetics, physiology)
• T-Lymphocytes, Cytotoxic (immunology)