The genes slyA, STM3120 and htrA are required for the anticancer ability of VNP20009

Abstract

VNP20009 is a very effective anti-cancer agent and can specifically target tumors and inhibit tumor growth. It was assumed that the tumor targeting ability of VNP20009 correlated to its anticancer capacity. However, our observation contradicted to this assumption. Three VNP20009 mutant strains ( ΔslyA , ΔSTM3120 and ΔhtrA ) with reduced fitness in normal tissues and unchanged fitness in tumors partially or completely lost their anti-cancer capacities. The genes slyA , STM3120 and htrA were required for survival within macrophages and were indispensable for tumor microenvironment remodeling by VNP20009. The infiltration of immune cells occurred less in the tumors of mice infected with the mutant strains. In addition, the mRNA levels of TNF-α and IL-1β were significantly decreased in the tumors of mice treated with the mutant strains. Our results indicate that the immune responses elicited by bacteria rather than the bacterial titer in tumors play a “decisive” role in VNP20009-mediated bacterial cancer therapy, which provides a novel perspective for the underlying mechanism of bacterial cancer therapy.

AttenuatedSalmonella VNP20009 mutant(ΔhtrA) is a promising candidate for bacteria-mediated tumour therapy in hosts with TNFR1 deficiency

“…Our previous studies found that ΔhtrA with impaired oxidative stress resistance can not engage in normal replication within macrophages (Zhang et al . ), because HtrA is a stress protein for degrading the damaged and misfolded proteins (Mutunga et al . ).…”

“…We previously reported that ΔhtrA exhibited therapeutic potentials with reduced colonization in normal organs and unchanged colonization in tumours (Zhang et al . ). Through systematic comparative toxicity and antitumour effect of VNP20009 and its mutant ΔhtrA in immunodeficient mice, we tried to provide preclinical data on tumour‐targeting Salmonella therapy.…”

Tumour-targeting bacteria engineered to fight cancer

“…In addition to the intrinsic antitumor effects, bacterial infection induces innate as well as adaptive immune responses against both tumor-colonizing bacteria and the tumor cells 46-48,52,55-59 . The host immune responses are more critical for the antitumor effects of bacteria such as Salmonella that are not sufficiently cytotoxic to tumor cells 55,60 . Numerous studies have suggested that both bacterium-intrinsic and host immune mechanisms are involved in tumor destruction (FIG.…”

A SARS-CoV-2 oral vaccine development strategy based on the attenuated Salmonella type III secretion system

“…Our preliminary study identified attenuated Salmonella VNP20009 as an effective plasmid delivery vector (Cheng et al, 2014 ) as well as a heterologous protein expression vector (Liu et al, 2015 ), and our previous research also successfully achieved a schistosome vaccine candidate based on an attenuated Salmonella vector (Chen et al, 2011 ). We also obtained an attenuated Salmonella mutant, Δ htrA ‐VNP, with a good safety profile, which has significantly reduced splenic and hepatic virulence compared with wild‐type VNP, making it suitable for vaccine or drug delivery vectors (Zhang et al, 2016 ). Here, we attempted to engineer Δ htrA ‐VNP as the SARS‐CoV‐2 antigen expression vector.…”