PURPOSE: We have shown tumor-targeting and antitumor activities of an attenuated Salmonella choleraesuis in various tumor models. Meanwhile, host factors, including innate and adaptive immune responses, play roles in Salmonella-induced antitumor activity. Toll-like receptor 4 (TLR4) is identified as a signaling receptor for lipopolysaccharide derived from Gram-negative bacteria. However, the detailed mechanism of the S. choleraesuis-induced antitumor immune response via TLR4 remained uncertain. EXPERIMENTAL DESIGN: Herein, we used wild-type C3H/HeN mice and TLR4-deficient C3H/HeJ mice to study the role of TLR4 in the antitumor immune responses induced by S. choleraesuis. RESULTS: The amounts of S. choleraesuis were cleared more rapidly from the normal organs in C3H/HeN mice than those in C3H/HeJ mice. Tumors in C3H/HeN mice treated with S. choleraesuis were significantly smaller than those treated with PBS. By contrast, in TLR4-deficient mice, there was a slight difference in inhibition of tumor growth. Meanwhile, we found that S. choleraesuis significantly up-regulated IFN-gamma, IFN-inducible chemokines CXCL9 (MIG), and CXCL10 (IP-10) productions in C3H/HeN mice, but not in C3H/HeJ mice. Furthermore, immunohistochemical staining of the tumors revealed less intratumoral microvessel density, more infiltration of macrophages, neutrophils, CD4(+) and CD8(+) T cells, and cell death in C3H/HeN mice after S. choleraesuis treatment compared with those in C3H/HeJ mice. The interaction between TLR4 and S. choleraesuis seemed to polarize the T-cell response to a T helper 1-dominant state. CONCLUSIONS: These results suggest TLR4 may play an important role in the molecular mechanism of S. choleraesuis-induced host antitumor responses.

Lee CH, Wu CL, Shiau AL.

Authors’ Affiliations: Departments of Microbiology and Immunology and Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.