An Enteric Pathogen Salmonella enterica serovar Typhimurium Suppresses Tumor Growth by Down Regulating CD44high and CD4 T Regulatory (Treg) Cell Expression in Mice: Critical Role of Lipopolysaccharide and Braun Lipoprotein in Modulating Tumor Growth

摘要

An anti-tumor activity associated with several bacterial pathogens, including Salmonella enterica serovar Typhimurium, has been reported; however, the underlying immunological mechanism(s) that leads to an anti-tumor effect is currently unclear. Further, such pathogens cannot be used to suppress tumor growth because of their potential for causing sepsis. Recently, we reported the characterization of S. Typhimurium isogenic mutants from which the Braun lipoprotein genes (lppA and B) and the multicopy repressor of high temperature requirement (msbB) gene were deleted. In a mouse infection model, two mutants, namely, lppB/msbB and lppAB/msbB, minimally induced proinflammatory cytokine production at high doses and were non-lethal to animals. We demonstrated that immunization of mice with these mutants, followed by challenge with the wild-type S. Typhimurium could significantly suppress tumor growth, as evidenced by an 88% regression in tumor size in lppB/msbB mutant-immunized animals over a 24-day period. However, the lppAB/msbB mutant alone was not effective in modulating tumor growth in mice, while the lppB/msbB mutant alone caused marginal regression in tumor size. Importantly, we demonstrated that CD44⁺ cells grew much faster than CD44⁻ cells from human liver tumors in mice, leading us to examine the possibility that S. Typhimurium might down-regulate CD44 in tumors and splenocytes of mice. Consequently, we found in S. Typhimurium-infected mice that tumor size regression could indeed be related to the down-regulation of CD44^high and CD4⁺CD25⁺ Treg cells. Importantly, the role of lipopolysaccharide and Braun lipoprotein was critical in S. Typhimurium induced-anti-tumor immune responses. Taken together, we have defined new immune mechanisms leading to tumor suppression in mice by S. Typhimurium.