Listeria monocytogenes Promotes Tumor Growth via Tumor Cell Toll-Like Receptor 2 Signaling

Abstract

The contribution of bacterial infection to tumorigenesis is usually ascribed to infection-associated inflammation. An alternate view is that direct interaction of bacteria with tumor cells promotes tumor progression. Here, we show that the microenvironment of large tumors favors bacterial survival, which in turn directly accelerates tumor growth by activating tumor cell Toll-like receptors (TLR). Listeria monocytogenes (Lm) survives in the microenvironment of large but not small tumors, resulting in the promotion of tumor growth. Lm did not affect the percentage of regulatory T cells or myeloid suppressor cells in the tumor. Through TLR2 signaling, Lm activated mitogen-activated protein kinases and nuclear factor-KB in tumor cells, resulting in the increased production of nitric oxide and interleukin-6 and increased proliferation of tumor cells. All of these effects were abrogated by silencing expression of TLR2, but not TLR4. The interaction of Helicobacter pylori with tumor cells from gastric carcinoma patients resulted in similar effects. These findings provide a new insight into infection-associated tumorigenesis and illustrate the importance of antibiotic therapy to treat tumors with bacterial infiltration. [Cancer Res 2007;67(9):4346-52]

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

“…We recently demonstrated that the level of TLR2 expressed on B16F10 melanoma cells determines their invasive activity in response to the endogenous factors released from tumor cells [12] . However, contradictory observations by others indicate that TLR2 activation is able to induce inflammatory cytokines and activate NK cells in vitro and in vivo and protect mice from tumor development and progression [31,32] . In the current study, we find that blocking TLR2 effectively reverses the immunosuppressive characteristics of the microenvironment by suppressing the expression of TGF-β1, IDO, and COX2 and attenuating the infiltration of M2 and Tregs cells.…”

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis

“…Although proof-ofprinciple for this concept has been demonstrated with agonists of several TLRs (TLR3, -7, and -9) (8), only one, the TLR7 agonist Imiquimod, has been approved for clinical use [however, this is limited to topical treatment of basal cell carcinoma (9)]. The major clinical limitations of many TLR agonists are the risk of dose-limiting toxicities associated with their systemic delivery (10)(11)(12) and metastasis stimulation (13)(14)(15). Furthermore, some previously investigated TLR agonists are restricted to injection directly into tumor tissue (3,(16)(17)(18), an approach that will likely have limited therapeutic value in cancer patients with metastatic disease.…”

Microparticles released by Listeria monocytogenes-infected macrophages are required for dendritic cell-elicited protective immunity

“…T cells stimulated by MPs-treated DCs were used as effector cells and Lminfected or uninfected H22 liver tumor cells (BALB/c background) were used as target cells. 18 We found that the effector T cells lysed Lm-infected H22 cells but not uninfected H22 cells (Figure 4a). Therefore, MPs from Lm-infected macrophages contained Lm components, which might induce T cells to kill Lm-infected cells.…”

“…18 Briefly, H22 hepatocarcinoma tumor cells were infected by incubation with Lm (1 : 100 ratio) for 2 h, and then cultured with 100 mg/ml of gentamycin for 24 h. Tumor cells were labeled with CFSE and used as target cells. After incubation with MPs isolated from the supernatants of Lm-infected macrophages, bone marrow-derived DCs were cultured with T cells for 10 days.…”